Biguanide compound and use thereof

ABSTRACT

The present invention relates to a guanidine compound and a use thereof, and more specifically, to a guanidine derivative showing excellent effects of inhibiting cancer cell proliferation, cancer metastasis, and cancer recurrence; a preparation method thereof; and a pharmaceutical composition containing the same as an active ingredient. Compared to existing drugs, the guanidine derivative according to the present invention shows excellent effects of inhibiting cancer cell proliferation, cancer metastasis, and cancer recurrence even with small doses, and may thus be effectively used in preventing or treating various cancers such as uterine cancer, breast cancer, stomach cancer, brain cancer, rectal cancer, colorectal cancer, lung cancer, skin cancer, blood cancer, liver cancer, etc., inhibiting cancer cell proliferation and cancer metastasis.

TECHNICAL FIELD

The present invention relates to a guanidine compound and a use thereof,and more specifically, to a guanidine derivative showing excellenteffects of inhibiting cancer cell proliferation, cancer metastasis, andcancer recurrence; a preparation method thereof, and a pharmaceuticalcomposition containing the same as an active ingredient.

BACKGROUND ART

While normal cells produce ATP via oxidative phosphorylation and rarelyproduce lactic acid, cancer cells produce ATP via glycolysis and lacticacid fermentation. Accordingly, unlike normal cells, cancer cellsrequire a higher amount of glucose, and glucose is converted by apro-oncogenic metabolism which prefers glycolysis even in an aerobicenvironment (Warburg effect). Cancer cells utilize such a metabolicpathway as a major source of energy supply for producing energy sources,and as such, cancer cells create an environment in which survival,proliferation, angiogenesis, and metastasis can occur actively, andprogress into a malignant tumor. Therefore, the inhibition of the energymetabolism by cancer cells will increase the likelihood of solving thenarrow therapeutic ranges of existing targeted cancer drugs andresistance thereof, and interests have recently been focused on thedevelopment of anticancer drugs targeting the metabolic characteristicsof these cancer cells (Nature Review cancer 2011; 11: 85-95).

The biguanide-based drugs such as phenformin and metformin are known asmitochondrial complex 1 inhibitor, and these drugs are known to inhibitdifferentiation and survival of cancer cells by increasing the energystress of the cancer cells via inhibition of their oxidativephosphorylation. However, the efficacies of these drugs are not strongenough and thus it is difficult for them to be developed into anticancerdrugs. In the case of phenformin, a biguanide-based drug, its use hasbeen fully prohibited since the late 1970s due to the side-effect ofsevere lactic acidosis. Accordingly, there is a need to develop abiguanide-based material with improved physicochemical propertiesexhibiting excellent pharmacological actions compared to the existingmetformin while not exhibiting any side-effects, as in phenformin.

DISCLOSURE Technical Problem

The present invention provides a novel guanidine derivative or apharmaceutically acceptable salt thereof which exhibits excellenteffects of inhibiting cancer cell proliferation, cancer metastasis, andcancer recurrence even with small doses compared to existing drugs, anda preparation method thereof.

Additionally, the present invention provides a pharmaceuticalcomposition for preventing or treating cancer containing the abovecompound or a pharmaceutically acceptable salt thereof as an activeingredient, and specifically, the cancer may be a disease selected fromthe group consisting of uterine cancer, breast cancer, stomach cancer,brain cancer, rectal cancer, colorectal cancer, lung cancer, skincancer, blood cancer, and liver cancer.

Technical Solution

An object of the present invention provides a novel guanidine derivativecompound or a pharmaceutically acceptable salt thereof selected from thegroup consisting of Compounds 1) to 165) described below.

Another object of the present invention provides a pharmaceuticalcomposition for preventing or treating cancer containing the abovecompound or a pharmaceutically acceptable salt thereof as an activeingredient.

Still another object of the present invention provides a use of theabove compound or a pharmaceutically acceptable salt thereof in thepreparation of a drug for treating cancer.

Still another object of the present invention provides a method forpreventing or treating cancer including administering a therapeuticallyeffective amount of the above compound or a pharmaceutically acceptablesalt thereof to a subject in need thereof.

Advantageous Effects of the Invention

Compared to existing drugs, the guanidine derivative according to thepresent invention shows excellent effects of inhibiting cancer cellproliferation, cancer metastasis, and cancer recurrence even with smalldoses, and may thus be effectively used in treating various cancers suchas uterine cancer, breast cancer, stomach cancer, brain cancer, rectalcancer, colorectal cancer, lung cancer, skin cancer, blood cancer, livercancer, etc., inhibiting cancer cell proliferation and cancermetastasis.

BEST MODE

In an aspect, the present invention provides a novel guanidinederivative compound selected from the group consisting of the followingCompounds 1) to 165) and a pharmaceutically acceptable salt thereof:

-   1) N1,N1-dimethyl-N5-piperidine biguanide,-   2) N1-piperidin-N5-piperidine biguanide,-   3) N1,N1-dimethyl-N5-methyl-N5-1-(naphthalen-1-yl)methyl biguanide,-   4) N1,N1-dimethyl-N5-(benzo[d][1,3]dioxol-5-yl)methyl biguanide,-   5) N1-piperidin-N5-pyrrolidine biguanide,-   6) N1-isopropyl-N5-1-(pyridin-3-yl)methyl biguanide,-   7) N1,N1-dipropyl-N5-propyl-N5-ethyl biguanide,-   8) N1,N1-dipropyl-N5-piperidine biguanide,-   9) N1-piperidin-N5-(benzo[d][1,3]dioxol-5-yl)methyl biguanide,-   10) N1-(4-chloro)phenyl-N5-t-butyl-N5-benzyl biguanide,-   11) N1-(3-bromo)phenyl-N5-(3-bromo)phenyl biguanide,-   12) N1-piperidin-N5-(2-chloro)benzyl biguanide,-   13) N1-piperidin-N5-(4-chloro)phenethyl biguanide.-   14) N1-piperidin-N5-(2-chloro)phenethyl biguanide,-   15) N1,N1-dipropyl-N5,N5-dicyclohexyl biguanide,-   16) N1,N1-dipropyl-N5,N5-dipropyl biguanide,-   17) N1-isopropyl-N5-(4-chloro)phenyl biguanide,-   18) N1-(4-methyl)piperazin-N5-(4-trifluoromethyl)benzyl biguanide,-   19) N1-(4-methyl)piperazin-N5-(4-trifluoromethyl)phenyl biguanide,-   20) N1-(4-methyl)piperazin-N5-(3-trifluoromethyl)benzyl biguanide,-   21) N1-(4-methyl)piperazin-N5-(3-trifluoromethyl)phenyl biguanide,-   22) N1-(4-methyl)piperazin-N5-(3-trifluoromethoxy)phenyl biguanide,-   23) N1-(4-ethoxy)piperidin-N5-(4-trifluoromethyl)phenyl biguanide,-   24) N1-(4-ethoxy)piperidin-N5-(3-trifluoromethyl)phenyl biguanide.-   25) N1-(4-ethoxy)piperidin-N5-(3-trifluoromethoxy)phenyl biguanide,-   26) N1-(4-ethoxy)piperidin-N5-(4-trifluoromethoxy)phenyl biguanide,-   27) N1-(4-methyl)piperazin-N5-(4-chloro)phenyl biguanide,-   28) N1-(4-methyl)piperazin-N5-(3-fluoro)phenyl biguanide,-   29) N1-(4-methyl)piperazin-N5-(3-chloro)phenyl biguanide,-   30) N1-(4-methyl)piperazin-N5-(2-chloro)phenyl biguanide,-   31) N1-(4-methyl)piperazin-N5-(4-chloro)benzyl biguanide,-   32) N1-(4-methyl)piperazin-N5-(2-chloro)benzyl biguanide,-   33) N1-(4-methyl)piperazin-N5-(4-fluoro)phenyl biguanide,-   34) N1-(4-methyl)piperazin-N5-(2-fluoro)phenyl biguanide,-   35) N1-(4-methyl)piperazin-N5-(3-chloro)benzyl biguanide,-   36) N1-(4-methyl)piperazin-N5-butyl biguanide,-   37) N1-(4-methyl)piperazin-N5-(3,4-dichloro)phenyl biguanide,-   38) N1-(4-methyl)piperazin-N5-(3,4-difluoro)phenyl biguanide,-   39) N1-(4-methyl)piperazin-N5-(3,5-difluoro)phenyl biguanide.-   40) N1-(4-methyl)piperazin-N5-(3,4,5-trifluoro)phenyl biguanide,-   41) N1-(3-pyridine)-N5-(3-trifluoromethyl)phenyl biguanide,-   42) N1-3-pyridin-N5-(3-trifluoromethoxy)benzyl biguanide,-   43) N1-3-pyridin-N5-(3-trifluoromethyl)benzyl biguanide,-   44) N1-(3-methyl)piperidin-N5-cyclopentyl biguanide,-   45) N1-(3-methyl)piperidin-N5-(4-methoxy)piperidine biguanide,-   46) N1-(3-methyl)piperidin-N5-(4-ethoxy)piperidine biguanide,-   47) N1-(3-methyl)piperidin-N5-pyrazin-2yl biguanide,-   48) N1-(4-methyl)piperidin-N5-(4-bromo)phenyl biguanide    hydrochloride,-   49) N1-(4-methyl)piperidin-N5-(3-trifluoromethoxy)phenyl biguanide,-   50) N1-(4-methyl)piperidin-N5-(3-trifluoromethyl)phenyl biguanide,-   51) N1-(3-methyl)piperidin-N5-(3-trifluoromethyl)phenyl biguanide,-   52) N1-(4-methyl)piperidin-N5-(4-trifluoromethoxy)phenyl biguanide,-   53) N1-(4-methyl)piperidin-N5-(4-trifluoromethyl)phenyl biguanide.-   54) N1-(4-methyl)piperidin-N5-(3-trifluoromethyl-4-fluoro)phenyl    biguanide,-   55) N1-(4-methyl)piperidin-N5-(4-chloro)phenyl biguanide,-   56) N1-(4-methyl)piperidin-N5-(4-fluoro)phenyl biguanide,-   57) N1-(4-methyl)piperidin-N5-(3-fluoro-4-trifluoromethyl)phenyl    biguanide,-   58) N1-(4-methyl)piperidin-N5-(3-trifluoromethyl-4-chloro)phenyl    biguanide,-   59) N1-(4-methyl)piperidin-N5-(3-fluoro-4-trifluoromethoxy)phenyl    biguanide,-   60) N1-(4-methyl)piperidin-N5-(3-trifluoromethyl)benzyl biguanide,-   61) N1-(4-methyl)piperidin-N5-(4-trifluoromethyl)benzyl biguanide,-   62) N1-(3,5-dimethyl)piperidin-N5-(4-trifluoromethoxy)phenyl    biguanide.-   63) N1-(3,5-dimethyl)piperidin-N5-(4-trifluoromethyl)phenyl    biguanide.-   64) N1-(3,5-dimethyl)piperidin-N5-(4-fluoro)phenyl biguanide,-   65) N1-(3,5-dimethyl)piperidin-N5-(3-trifluoromethyl-4-fluoro)phenyl    biguanide,-   66) N1-2,5-dihydro-1H-pyrrol-N5-pyridin-3-yl biguanide,-   67) N1-2,5-dihydro-1H-pyrrol-N5-2,5-dihydro-1H-pyrrole biguanide,-   68) N1-1,2,3,6-tetrahydropyridin-N5-1,2,3,6-tetrahydropyridine    biguanide,-   69) N1-(4-methyl)piperidin-N5-(4-aminoethyl)phenyl biguanide,-   70) N1-pyrrolidin-N5-(4-acetyl)phenyl biguanide,-   71) N1-piperidin-N5-(4-morpholin-4-yl)phenyl biguanide,-   72) N1-pyrrolidin-N5-(4-bromo)phenyl biguanide,-   73) N1-piperidin-N5-(4-methoxy)phenyl biguanide.-   74) N1-piperidin-N5-(2-propyl)phenyl biguanide,-   75) N1-pyrrolidin-N5-(2-trifluoromethyl)phenyl biguanide,-   76) N1-pyrrolidin-N5-(2-chloro-5-trifluoromethyl)phenyl biguanide,-   77) N1-pyrrolidin-N5-(3-chloro-4-fluoro)phenyl biguanide,-   78) N1-pyrrolidin-N5-(2,3-dichloro)phenyl biguanide,-   79) N1-pyrrolidin-N5-(4-trifluoromethylthio)phenyl biguanide,-   80) N1-pyrrolidin-N5-(2,6-difluoro)phenyl biguanide.-   81)    (3-(3-(imino(piperidin-1-yl)methyl)guanidino)benzyl)triphenylphosphonium    chloride,-   82) N1-pyrrolidin-N5-methyl-N5-(4-trifluoromethoxy)phenyl biguanide,-   83) N1-pyrrolidin-N5-(4-phenoxy)phenyl biguanide.-   84) N1,N1-dimethyl-N5-(4-trifluoromethoxy)phenyl biguanide,-   85) N1,N1-dimethyl-N5-methyl-N5-(4-trifluoromethoxy)phenyl    biguanide,-   86) N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N5-(2-thiophen-2-yl)ethyl    biguanide.-   87) N1-(N-acetyl)piperazin-N5-(4-trifluoromethoxy)phenyl biguanide,-   88) N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N5-butyl biguanide,-   89) N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N5-phenethyl biguanide,-   90) N1-(4,4-difluoro)piperidin-N5-(3,4-dichloro)phenyl biguanide,-   91) N1-(4,4-difluoro)piperidin-N5-5,6,7,8-tetrahydronaphthalen-2-yl    biguanide,-   92) N1-butyl-N2-cycloheptyl biguanide,-   93) N1,N1-dimethyl-N2-(4-fluoro)benzyl-N5-piperidine biguanide,-   94) N1-phenyl-N2-phenethyl biguanide,-   95) N1-phenethyl-N2-(4-bromo)phenyl biguanide,-   96) N1-benzyl-N2-methyl-N5,N5-dimethyl biguanide,-   97) N1-phenethyl-N2-methyl-N5,N5-dimethyl biguanide,-   98) N1-(4-chloro)benzyl-N2-cycloheptyl biguanide,-   99) N1-piperidin-N2-(2-thiophen-2-yl)ethyl biguanide,-   100) N1-(benzo[d][1,3]dioxol-5-yl)methyl-N2-ethyl biguanide,-   101) N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N2-ethyl biguanide,-   102) N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N2-methyl biguanide,-   103) N1-(2-thiophen-2-yl)ethyl-N2-phenethyl biguanide,-   104) N1-(2-thiophen-2-yl)ethyl-N2-2-(benzo[d][1,3]dioxol-5-yl)ethyl    biguanide,-   105) N1-(4-trifluoromethoxy)phenyl-N2-methyl-N5-pyrrolidine    biguanide,-   106)    N1-methyl-N1-(4-trifluoromethoxy)phenyl-N2-methyl-N5-pyrrolidine    biguanide,-   107) N1-(benzo[d][1,3]dioxol-5-yl)methyl-N2-cyclopentyl biguanide.-   108) N1-methyl biguanide,-   109) N1-hexyl biguanide.-   110) N1-(4-chloro)phenyl biguanide,-   111) N1-(2-propene) biguanide,-   112) N1-(benzo[d][1,3]dioxol-5-yl)methyl biguanide,-   113) N1-phenyl biguanide,-   114) N1-propyl biguanide,-   115) N1,N1-diisopropyl biguanide,-   116) N1-(4-bromo)phenyl biguanide,-   117) N1-(4-acetyl)phenyl biguanide,-   118) N1-morpholin-4-yl biguanide,-   119) N1-(2-trifluoromethyl)phenyl biguanide.-   120) N1-(4-methoxy)phenyl biguanide,-   121) N1-(2-propyl)phenyl biguanide,-   122) N1-(4-morpholin-4-yl)phenyl biguanide.-   123) N1-piperidine biguanide,-   124) N1-benzyl biguanide,-   125) N1-4-(N-acetylamino)phenyl biguanide,-   126) N1-pyrrolidine biguanide,-   127) N1-4-(pyridin-2-yl)piperazine biguanide,-   128) N1-(4-trifluoromethyl)phenyl biguanide,-   129) N1-(4-chloro)benzyl biguanide,-   130) N1,N1-dibenzyl biguanide,-   131) N1-(4-methoxy)benzyl biguanide,-   132) N1-(4-fluoro)benzyl biguanide,-   133) N1,N1-dihexyl biguanide.-   134) N1-methyl-N1-butyl biguanide,-   135) N1-methyl-N1-cyclohexyl biguanide,-   136) N1,N1-dicyclohexyl biguanide,-   137) N1-(4-chloro)phenethyl biguanide,-   138) N1-(4-hydroxy)phenethyl biguanide,-   139) N1-azepane biguanide,-   140) N1-(4-trifluoromethoxy)phenyl biguanide,-   141) N1-(4-trifluoromethyl)benzyl biguanide,-   142) N1-(4-trifluoromethoxy)benzyl biguanide,-   143) N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl biguanide,-   144) N1-(furan-2-y)methyl biguanide,-   145) N1-(2-thiophen-2-yl)ethyl biguanide,-   146) N1-(2-fluoro-4-hydroxy)benzyl biguanide,-   147) N1-(4-fluoro)phenylpropyl biguanide,-   148) N1-(4-methoxy)phenylpropyl biguanide,-   149) N1-(2-iodo)benzyl biguanide,-   150) N1-(3-iodo)benzyl biguanide,-   151)    N-(6,6-dimethyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,-   152)    1-(6,6-dimethyl-4-oxo-1,4,5,6-tetrahydropyrimidin-3-yl)guanidine,-   153)    N-(1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,-   154)    N-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,-   155)    N-(5-methyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide.-   156)    N-(4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,-   157)    N-(6-cyclopropyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide    hydrochloride,-   158)    N-(5-methyl-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide.-   159)    N-(6-isopropyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,-   160) 1-(5-methyl-4-oxo-1,4,5,6-tetrahydropyrimidin-3-yl)guanidine,-   161)    N-(6-isobutyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,-   162)    N-(4-methyl-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,-   163)    N-(6-propyl-4-oxo-1,4,5,6-tetrahydroprimidin-2-yl)piperidin-1-carboximidamide,-   164) 1-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrimidin-3-yl)guanidine,    and-   165)    N-(4-ethyl-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide.

The N1,N1-dimethyl-N5-piperidine biguanide compound according to thepresent invention may be prepared by an illustrative method shown inReaction Scheme 1 below. Furthermore, among the compounds according tothe present invention, the compounds with a biguanide structure havingsubstituents at N1 and N5 may be prepared by a method varying only thecyanoguanidine and amine compounds in Reaction Scheme 1 below.

Specifically, piperidine was dissolved in n-butanol and then 1equivalent of the cyanoguanidine compound and 1 equivalent ofconcentrated hydrochloric acid were added thereto and the mixture wasstirred under reflux for 15 hours. Once the reaction is completed, acompound can be obtained by solvent evaporation under reduced pressureand purification.

The N1-butyl-N2-cycloheptyl biguanide hydrochloride compound accordingto the present invention may be prepared by an illustrative method shownin Reaction Scheme 2 below. Furthermore, among the compounds accordingto the present invention, the compounds with a biguanide structurehaving substituents at N1 and N2 may be prepared by a method varyingonly the thiourea and guanidine compounds in Reaction Scheme 2 below.

Specifically, the thiourea compound was dissolved in ethanol and then 3equivalents of guanidine hydrochloride and 2 equivalents of mercuryoxide were added thereto and the mixture was stirred under reflux for 1hour. Once the reaction is completed, a compound can be obtained byfiltration, evaporation of the solvent under reduced pressure andpurification.

The N1-methyl biguanide hydrochloride compound according to the presentinvention may be prepared by an illustrative method shown in ReactionScheme 3 below. Furthermore, among the compounds according to thepresent invention, the biguanide compounds having a substituent at N1may be prepared by a method varying only the amine compound in ReactionScheme 3 below.

Specifically, the amine compound was dissolved in n-butanol and then 1equivalent of the cyanoguanidine compound and 1 equivalent ofconcentrated hydrochloric acid were added thereto and the mixture wasstirred under reflux for 15 hours. Once the reaction is completed, acompound can be obtained by solvent evaporation under reduced pressureand purification.

TheN-(6,6-dimethyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamidehydrochloride compound according to the present invention may beprepared by an illustrative method shown in Reaction Scheme 4 below.Furthermore, among the compounds according to the present invention, theguanide compounds having a structure of tetrahydropyrimidine may beprepared by a method varying only the cyanoguanidine and amine compoundsin Reaction Scheme 3 below.

Specifically, the aminobutanoate compound was dissolved in ethanol andthen 1 equivalent of the cyanoguanidine compound was added thereto andthe mixture was stirred under reflux for 15 hours. Once the reaction iscompleted, a compound can be obtained by solvent evaporation underreduced pressure and purification.

Meanwhile, the pharmaceutically acceptable salt of the above compoundsaccording to the present invention may be an acid addition salt formedusing an organic or inorganic acid. Examples of the organic acid mayinclude formic acid, acetic acid, propionic acid, lactic acid, butyricacid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid,malonic acid, fumaric acid, succinic acid, succinic acid monoamide,glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid,glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylicacid, anthranilic acid, dichloroacetic acid, aminooxyacetic acid,benzenesulfonic acid, 4-toluenesulfonic acid, and methanesulfonic acid.Examples of the inorganic acid may include hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonicacid, and boric acid. The acid addition salt mentioned above may beprepared by applying to the conventional methods of salt preparation,for example, by a) directly mixing the compound above with an acid, b)mixing any of these by dissolving in a solvent or water-containingsolvent, or c) mixing the compound above with an acid in the presence ofa solvent or hydrated solvent.

In a specific embodiment, the pharmaceutically acceptable salt of thecompound may be a salt with an acid selected from the group consistingof formic acid, acetic acid, propionic acid, lactic acid, butyric acid,isobutyric acid, trifluoroacetic acid, malic acid, maleic acid, malonicacid, fumaric acid, succinic acid, succinic acid monoamide, glutamicacid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronicacid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid,anthranilic acid, benzenesulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, dichloroacetic acid, aminooxyacetic acid,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acidnitric acid, carbonic acid, and boric acid.

Another aspect of the present invention provides a pharmaceuticalcomposition containing the guanidine derivative compound or apharmaceutically acceptable salt thereof as an active ingredient. Thepharmaceutical composition according to the present invention has anexcellent effect of inhibiting the proliferation of cancer cells and canthus be used for preventing or treating various cancers. Accordingly,the present invention provides a use of the guanidine derivativecompound or a pharmaceutically acceptable salt thereof for preventing ortreating cancer, and a method for preventing or treating cancerincluding administering a therapeutically effective amount of thecompound or a pharmaceutically acceptable salt thereof to a subject inneed thereof.

In a specific embodiment, the cancer may include uterine cancer, breastcancer, stomach cancer, brain cancer, rectal cancer, colorectal cancer,lung cancer, skin cancer, blood cancer, and liver cancer, but is notlimited thereto.

The pharmaceutical composition of the present invention may include atleast one pharmaceutically acceptable carrier, in addition to activeingredients. As used herein, the term “pharmaceutically acceptablecarrier” refers to a pharmaceutical excipient, which is useful informulating pharmaceutically active compounds for administration andknown as substantially non-toxic and non-sensitive under the conditionsof use. The exact ratio of the excipient may be determined not only bythe solubility, chemical properties, selected routes of administrationof an active compound, but also by the standard pharmaceuticalpractices.

The pharmaceutical composition of the present invention may beformulated into a form suitable for the desired administration method,using additives such as an appropriate and physiologically acceptableexcipient, disintegrant, sweetener, binder, coating agent, swellingagent, lubricant, glidant, flavoring agent, etc.

The pharmaceutical composition may be formulated into tablets, capsules,pills, granules, powders, injections, and liquids, but is not limitedthereto.

The formulations of the pharmaceutical composition and pharmaceuticallyacceptable carriers may be appropriately selected according to thetechnologies known in the art.

Meanwhile, as used herein, the term “subject” refers to a warm-bloodedanimal such as a mammal which has a particular disease, disorder, orillness, for example, humans, orangutans, chimpanzees, mice, rats, dogs,cows, chickens, pigs, goats, sheep, etc., but the animal is not limitedthereto.

As used herein, the term “treatment” refers to any action to alleviatesymptoms, to temporarily or permanently eliminate the cause(s) ofsymptoms, and to prevent or delay the occurrence of symptoms and theprogress of the diseases, disorders, and illnesses described above, butis not limited thereto.

As used herein, the term “effective amount” of an active ingredient ofthe pharmaceutical composition of the present invention refers to theamount required for achieving the treatment of a given disease.Accordingly, the effective amount may be adjusted according to variousfactors including the type of a disease, severity of illness, and kindsand amounts of active ingredients and other ingredients contained in acomposition, formulation type, age, weight, general health conditions,sex, and diets of a patient, duration and route of administration,release rate of a composition, duration of treatment, and drugs used incombination. For adults, for example, the compound or a pharmaceuticallyacceptable salts thereof according to the present invention may beadministered once or a few times daily, in an amount of a total of 50mg/kg to 3000 mg/kg. However, the amount for administration may varyaccording to various factors illustrated above, and may be administeredin a lesser amount or a higher amount compared to the above range of theamount for administration depending on the cases.

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the present invention will be described in more detail withreference to the following Examples. However, these Examples are forillustrative purposes only and the invention is not intended to belimited by these Examples.

Example 1: Synthesis of N1,N1-dimethyl-N5-piperidine biguanidehydrochloride

Piperidine (0.85 g, 9.98 mmol) was dissolved in n-butanol (20 mL) atroom temperature. N,N-dimethylcyanoguanidine (1.12 g, 9.98 mmol) andconcentrated hydrochloric acid (0.9 mL, 9.98 mmol) were added theretoand stirred under reflux for 15 hours. The reaction mixture wasconcentrated under reduced pressure and separated and purified using achromatography in a condition where the ratio of methylene chloride (MC)to methyl alcohol (MeOH) was 9:1 and the target compound was obtained asa white solid (1.5 g, 64.0%).

¹H NMR (600 MHz, DMSO) δ2.90 (t. J=6 Hz, 4H), 2.82 (s, 6H), 1.64 (m,4H), 1.49 (m, 2H)

LCMS: 198.0 [M+H]⁺

Example 2: Synthesis of N1-piperidin-N5-piperidine biguanidehydrochloride

The target compound was obtained as a white solid (1.28 g, 47.0%) in thesame manner as in Example 1, except that piperidine cyanoguanidine wasused instead of N,N-dimethylcyanoguanidine.

¹H NMR (600 MHz, DMSO) δ2.93 (t, J=6 Hz, 8H), 1.62 (m, 8H), 1.47 (m, 4H)

LCMS: 238.0 [M+H]⁺

Example 3: Synthesis ofN1,N1-dimethyl-N5-methyl-N5-1-(naphthalen-1-yl)methyl biguanidehydrochloride

The target compound was obtained as a white solid (0.62 g, 70.7%) in thesame manner as in Example 1, except thatN-methyl-1-(naphthalen-1-yl)methanamine was used instead of piperidine.

¹H NMR (600 MHz, DMSO) δ 8.26 (d, J=8.4 Hz), 8.02 (d, J=8.4 Hz, 1H),7.79 (d, J=8.4 Hz, 1H), 7.57 (m, 4H), 4.61 (s, 2H), 3.05 (s, 9H)

LCMS: 284.0 [M+H]⁺

Example 4: Synthesis ofN1,N1-dimethyl-N5-(benzo[d][1,3]dioxol-5-yl)methyl biguanidehydrochloride

The target compound was obtained as a white solid (1.8 g, 60.0%) in thesame manner as in Example 1, except that benzo[d][1,3]dioxol-5-ylmethanamine was used instead of piperidine.

¹H NMR (600 MHz, DMSO) δ7.06 (s, 1H), 6.90 (s, 2H), 5.99 (s, 2H), 3.87(s, 2H), 3.32 (s, 6H)

LCMS: 264.0 [M+H]⁺

Example 5: Synthesis of N1-piperidin-N5-pyrrolidine biguanidehydrochloride

The target compound was obtained as a white solid (0.65 g, 50.0%) in thesame manner as in Example 1, except that piperidine cyanoguanidine andpyrrolidine were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (600 MHz, DMSO) δ3.07 (m, 2H), 2.97 (t, J=6 Hz, 6H), 1.83 (m,2H), 1.69 (m, 6H), 1.54 (m, 2H)

LCMS: 224.1 [M+H]⁺

Example 6: Synthesis of N1-isopropyl-N5-1-(pyridin-3-yl)methyl biguanidehydrochloride

The target compound was obtained as a white solid (0.11 g, 15.0%) in thesame manner as in Example 1, except that isopropylcyanoguanidine and1-(pyridin-3-yl)methanamine were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ8.52 (s, 1H), 8.46 (m, 1H), 7.72 (m, 1H), 7.37(m, 1H), 4.37 (s, 2H), 3.65 (m, 1H), 1.04 (s, 6H)

LCMS: 235.1 [M+H]⁺

Example 7: Synthesis of N1,N1-dipropyl-N5-propyl-N5-ethyl biguanidehydrochloride

The target compound was obtained as a white solid (0.52 g, 30.2%) in thesame manner as in Example 1, except that N,N-diisopropylcyanoguanidineand N-ethylpropan-1-amine were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ2.86 (m, 4H), 2.77 (m, 4H), 1.57 (m, 6H), 1.15(m, 6H), 0.87 (m, 6H)

LCMS: 256.1 [M+H]⁺

Example 8: Synthesis of N1,N1-dipropyl-N5-piperidine biguanidehydrochloride

The target compound was obtained as a white solid (0.60 g, 31.0%) in thesame manner as in Example 1, except that N,N-dipropylcyanoguanidine wasused instead of N,N-dimethylcyanoguanidine.

¹H NMR (600 MHz, DMSO) δ3.22 (m, 8H), 1.53 (m, 8H), 0.91 (m, 8H)

LCMS: 254.1 [M+H]⁺

Example 9: Synthesis of N1-piperidin-N5-(benzo[d][1,3]dioxol-5-yl)methylbiguanide hydrochloride

The target compound was obtained as a white solid (1.00 g, 40.0%) in thesame manner as in Example 1, except that piperidine cyanoguanidine andbenzo[d][1,3]dioxol-5-ylmethanamine were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ7.04 (s, 1H), 6.93 (s, 2H), 5.97 (s, 2H), 3.87(s, 2H), 3.33 (m, 4H), 1.62 (m, 4H), 1.47 (m, 2H)

LCMS: 304.1 [M+H]⁺

Example 10: Synthesis of N1-(4-chloro)phenyl-N5-t-butyl-N5-benzylbiguanide hydrochloride

The target compound was obtained as a white solid (0.56 g, 57.0%) in thesame manner as in Example 1, except that 4-chlorophenylcyanoguanidineand N-benzyl-2-methylpropan-2-amine were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ7.66 (m, 4H), 7.38 (m, 5H), 4.07 (s, 2H), 1.42(s, 9H)

LCMS: 358.1 [M+H]⁺

Example 11: Synthesis of N1-(3-bromo)phenyl-N5-(3-bromo)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.58 g, 26.0%) in thesame manner as in Example 1, except that 3-bromophenyl cyanoguanidineand 3-bromoaniline were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (600 MHz, DMSO) δ7.58 (s, 2H), 7.29 (m, 6H)

LCMS: 411.1 [M+H]⁺

Example 12: Synthesis of N1-piperidin-N5-(2-chloro)benzyl biguanidehydrochloride

The target compound was obtained as a white solid (0.43 g, 41.3%) in thesame manner as in Example 1, except that piperidine cyanoguanidine and2-chlorobenzylamine were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (6000 MHz, DMSO) δ7.60 (m, 1H), 7.42 (m, 1H), 7.25 (m, 2H), 4.00(s, 2H), 2.93 (m, 4H), 1.65 (m, 4H), 1.52 (m, 2H)

LCMS: 294.1 [M+H]⁺

Example 13: Synthesis of N1-piperidin-N5-(4-chloro)phenethyl biguanidehydrochloride

The target compound was obtained as a white solid (0.42 g, 36.8%) in thesame manner as in Example 1, except that piperidine cyanoguanidine and4-chlorophenethylamine were used instead of N,N-dimethylcyanoguanidineand piperidine.

¹H NMR (600 MHz, CD₃OD) δ7.40 (m, 2H), 3.01 (m, 8H), 1.70 (m, 4H), 1.55(m, 2H)

LCMS: 308.1 [M+H]⁺

Example 14: Synthesis of N1-piperidin-N5-(2-chloro)phenethyl biguanidehydrochloride

The target compound was obtained as a white solid (0.42 g, 36.8%) in thesame manner as in Example 1, except that piperidine cyanoguanidine and2-chlorophenethylamine were used instead of N,N-dimethylcyanoguanidineand piperidine.

¹H NMR (600 MHz, CD₃OD) δ7.38 (m, 2H), 3.03 (m, 8H), 1.68 (m, 4H), 1.53(m, 2H)

LCMS: 308.1 [M+H]⁺

Example 15: Synthesis of N1,N1-dipropyl-N5,N5-dicyclohexyl biguanidehydrochloride

The target compound was obtained as a white solid (0.27 g, 21.1%) in thesame manner as in Example 1, except that N,N-propylcyanoguanidine anddicyclohexylamine were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (600 MHz, DMSO) δ2.55 (m, 6H), 1.49 (m, 20H), 1.44 (m, 4H), 0.96(m, 6H)

LCMS: 350.1 [M+H]⁺

Example 16: Synthesis of N1,N1-dipropyl-N5,N5-dipropyl biguanidehydrochloride

The target compound was obtained as a white solid (0.36 g, 25.0%) in thesame manner as in Example 1, except that N,N-dipropylcyanoguanidine anddipropylamine were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (600 MHz, DMSO) δ3.30 (m, 8H), 1.48 (m, 8H), 0.80 (m, 12H)

LCMS: 270.2 [M+H]⁺

Example 17: Synthesis of N1-isopropyl-N5-(4-chloro)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (3.00 g, 45.0%) in thesame manner as in Example 1, except that isopropylcyanoguanidine and2-chloroaniline were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (600 MHz, DMSO) δ7.17 (d, J=7.8 Hz, 2H), 6.40 (d, J=7.8 Hz, 2H),2.97 (m, 1H), 1.05 (m, 6H)

LCMS: 254.1 [M+H]⁺

Example 18: Synthesis ofN1-(4-methyl)piperazin-N5-(4-trifluoromethyl)benzyl biguanidehydrochloride

The target compound was obtained as a white solid (0.29 g, 40.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 4-trifluoromethyl benzylamine wereused instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ7.70 (d, J=7.8 Hz, 2H), 7.52 (d, J=7.8 Hz, 2H),4.40 (d, J=5.4 Hz, 2H), 3.33 (m, 4H), 2.25 (m, 4H), 2.16 (s, 3H)

LCMS: 343.2 [M+H]⁺

Example 19: Synthesis ofN1-(4-methyl)piperazin-N5-(4-trifluoromethyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.18 g, 10.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 4-trifluoromethylaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ7.64 (m, 4H), 3.30 (m, 4H), 2.25 (m, 4H), 2.19(s, 3H)

LCMS: 329.2 [M+H]⁺

Example 20: Synthesis ofN-(4-methyl)piperazin-N5-(3-trifluoromethyl)benzyl biguanidehydrochloride

The target compound was obtained as a white solid (0.15 g, 23.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 3-trifluoromethylbenzylamine wereused instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz. DMSO) δ7.62 (m, 4H), 4.41 (d, J=6 Hz, 2H), 3.48 (m,4H), 2.60 (m, 4H), 2.36 (s, 3H)

LCMS: 343.2 [M+H]⁺

Example 21: Synthesis ofN1-(4-methyl)piperazin-N5-(3-trifluoromethyl)phenyl biguanide

The target compound was obtained as a white solid (0.51 g, 52.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 3-trifluoromethylaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ7.82 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.54 (t,J=8.4 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 3.47 (m, 4H), 2.34 (m, 4H), 2.19(s, 3H)

LCMS: 329.2 [M+H]⁺

Example 22: Synthesis ofN1-(4-methyl)piperazin-N5-(3-trifluoromethoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.10 g, 15.5%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 3-trifluoromethoxyaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ7.52 (s, 1H), 7.42 (t. J=8.4 Hz, 1H), 7.30 (d,J=8.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 3.47 (m, 4H), 2.35 (m, 4H), 2.19(s, 3H)

LCMS: 345.2 [M+H]⁺

Example 23: Synthesis ofN1-(4-ethoxy)piperidin-N5-(4-trifluoromethyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.04 g, 47.0%) in thesame manner as in Example 1, except that 4-ethoxypiperidinecyanoguanidine and 3-trifluoromethylaniline were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz. DMSO) δ7.64 (m, 4H), 3.70 (m, 3H), 3.48 (m, 2H), 3.28(m, 2H), 1.86 (m, 2H), 1.52 (m, 2H), 1.12 (m, 3H)

LCMS: 358.2 [M+H]⁺

Example 24: Synthesis ofN1-(4-ethoxy)piperidin-N5-(3-trifluoromethyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.12 g, 60.6%) in thesame manner as in Example 1, except that 4-ethoxypiperidinecyanoguanidine and 3-trifluoromethylaniline were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ7.60 (d, J=7.8 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H),7.36 (d, J=7.8 Hz, 1H), 7.00 (s, 1H), 3.71 (m, 2H), 3.53 (m, 2H), 3.28(m, 2H), 1.85 (m, 2H), 1.50 (m, 2H), 1.10 (m, 3H)

LCMS: 358.2 [M+H]⁺

Example 25: Synthesis ofN1-(4-ethoxy)piperidin-N5-(3-trifluoromethoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.10 g, 48.3%) in thesame manner as in Example 1, except that 4-ethoxypiperidinecyanoguanidine and 3-trifluoromethoxyaniline were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ7.52 (s, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.30 (d,J=8.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 3.71 (m, 2H), 3.67 (m, 2H), 3.28(m, 2H), 1.84 (m, 2H), 1.50 (m, 2H), 1.11 (m, 3H)

LCMS: 374.2 [M+H]⁺

Example 26: Synthesis ofN1-(4-ethoxy)piperidin-N5-(4-trifluoromethoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.09 g, 44.7%) in thesame manner as in Example 1, except that 4-ethoxypiperidinecyanoguanidine and 4-trifluoromethylaniline were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ7.47 (m, 2H), 7.30 (m, 2H), 3.66 (m, 2H), 3.53(m, 2H), 3.24 (m, 2H), 1.83 (m, 2H), 1.49 (m, 2H), 1.12 (m, 3H)

LCMS: 374.2 [M+H]⁺

Example 27: Synthesis of N1-(4-methyl)piperazin-N5-(4-chloro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.09 g, 27.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 4-chloroaniline were used insteadof N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ7.39 (m, 4H), 3.45 (m, 4H), 2.34 (m, 4H), 2.19(s, 3H)

LCMS: 295.2 [M+H]⁺

Example 28: Synthesis of N1-(4-methyl)piperazin-N5-(3-fluoro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.12 g, 44.3%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 3-fluoroaniline were used insteadof N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ7.36 (d, J=12 Hz, 1H), 7.31 (m, 1H), 7.11 (d,J=7.8 Hz, 1H), 6.85 (t, J=7.8 Hz, 1H), 3.34 (m, 4H), 2.83 (m, 4H), 2.19(s, 3H)

LCMS: 279.2 [M+H]⁺

Example 29: Synthesis of N1-(4-methyl)piperazin-N5-(3-chloro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.02 g, 6.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 3-fluoroaniline were used insteadof N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, DMSO) δ7.29 (m, 1H), 7.09 (m, 1H), 7.02 (m, 1H), 6.89(m, 1H), 3.39 (m, 4H), 2.31 (m, 4H), 2.13 (s, 3H)

LCMS: 295.4 [M+H]⁺

Example 30: Synthesis of N1-(4-methyl)piperazin-N5-(2-chloro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.04 g, 1.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 2-chloroaniline were used insteadof N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.43 (m, 1H), 7.25 (m, 1H), 7.08 (m, 1H), 6.98(m, 1H), 3.34 (s, 4H), 2.37 (s, 4H), 2.17 (s, 3H)

LCMS: 295.4 [M+H]⁺

Example 31: Synthesis of N1-(4-methyl)piperazin-N5-(4-chloro)benzylbiguanide hydrochloride

The target compound was obtained as a white solid (0.02 g, 7.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 4-chlorobenzylamine were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.12 (m, 4H), 4.17 (s, 2H), 3.27 (s, 4H), 2.25(s, 4H), 2.14 (s, 3H)

LCMS: 309.4 [M+H]⁺

Example 32: Synthesis of N1-(4-methyl)piperazin-N5-(2-chloro)benzylbiguanide hydrochloride

The target compound was obtained as a white solid (0.02 g, 6.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 2-chlorobenzylamine were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.42 (m, 2H), 7.31 (m, 2H), 4.52 (s, 2H), 3.76(s, 4H), 3.07 (s, 4H), 2.70 (s, 3H)

LCMS: 309.4 [M+H]⁺

Example 33: Synthesis of N1-(4-methyl)piperazin-N5-(4-fluoro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.10 g, 36.1%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 4-fluoroaniline were used insteadof N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, DMSO-d₆) δ7.76 (s, 1H), 7.37 (m, 1H), 7.12 (t, 1H), 7.02(s, 1H) 3.46 (m, 4H), 2.33 (m, 4H), 2.19 (s, 3H)

LCMS: 279.4 [M+H]⁺

Example 34: Synthesis of N1-(4-methyl)piperazin-N5-(2-fluoro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.10 g, 35.9%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 2-fluoroaniline were used insteadof N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, DMSO-d₆) δ7.75 (s, 1H), 7.15 (m, 2H), 7.13 (s, 1H), 3.43(s, 4H), 2.38 (s, 4H), 2.19 (s, 3H)

LCMS: 279.4 [M+H]⁺

Example 35: Synthesis of N1-(4-methyl)piperazin-N5-(3-chloro)benzylbiguanide hydrochloride

The target compound was obtained as a white solid (0.03 g, 0.8%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 3-chlorobenzylamine were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.31 (m, 4H), 4.18 (s, 2H), 3.47 (s, 4H), 2.44(s, 4H), 2.31 (s, 3H)

LCMS: 309.4 [M+H]⁺

Example 36: Synthesis of N1-(4-methyl)piperazin-N5-butyl biguanidehydrochloride

The target compound was obtained as a white solid (0.22 g, 41.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 1-butylamine were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz. CD₃OD) δ4.29 (m, 2H), 3.71 (s, 4H), 3.50 (m, 3H), 2.98(m, 4H), 1.68 (m, 2H), 1.45 (m, 2H), 0.98 (m, 3H)

LCMS: 241.2 [M+H]⁺

Example 37: Synthesis of N1-(4-methyl)piperazin-N5-(3,4-dichloro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.06 g, 12.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 3,4-dichloroaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.38 (s, 2H), 7.19 (s, 1H), 3.69 (m, 4H), 3.52(t, 3H), 2.97 (s, 4H)

LCMS: 329.1, 331.1 [M, M+2]⁺

Example 38: Synthesis of N1-(4-methyl)piperazin-N5-(3,4-difluoro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.06 g, 18.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 3,4-difluoroaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz; CD₃OD) δ7.43 (m, 1H), 7.22 (q, 1H), 7.07 (m, 1H), 3.57(t, 4H), 2.50 (t, 4H), 2.34 (s, 3H)

LCMS: 297.2 [M+H]⁺

Example 39: Synthesis of N1-(4-methyl)piperazin-N5-(3,5-difluoro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.49 g, 13.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 3,5-difluoroaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.04 (m, 2H), 6.65 (m, 1H), 3.61 (m, 4H), 2.53(m, 4H), 2.34 (s, 3H)

LCMS: 297.2 [M+H]⁺

Example 40: Synthesis ofN1-(4-methyl)piperazin-N5-(3,4,5-trifluoro)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.12 g, 40.0%) in thesame manner as in Example 1, except that4-methylpiperazinecyanoguanidine and 3,4,5-trifluoroaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.20 (m, 2H), 3.58 (m, 4H), 2.52 (m, 4H), 2.34(s, 3H)

LCMS: 315.2 [M+H]⁺

Example 41: Synthesis of N1-3-pyridin-N5-(3-trifluoromethyl)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.25 g, 43.0%) in thesame manner as in Example 1, except that 3-pyridinecyanoguanidine and3-trifluoroaniline were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (600 Hz, CD₃OD) δ8.56 (m, 2H), 8.33 (s, 1H), 7.85 (d, 1H), 7.67(s, 1H), 7.52 (m, 2H), 7.45 (m, 1H)

LCMS: 323.2 [M+H]⁺

Example 42: Synthesis of N1-3-pyridin-N5-(3-trifluoromethoxy)benzylbiguanide hydrochloride

The target compound was obtained as a white solid (0.20 g, 37.0%) in thesame manner as in Example 1, except that 3-pyridinecyanoguanidine and4-trifluoromethoxybenzylamine were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ8.48 (s, 1H), 8.00 (d, 1H), 7.82 (s, 1H), 7.75(s, 1H), 7.51 (s, 1H), 7.31 (m, 4H), 4.50 (m, 2H)

LCMS: 353.2 [M+H]⁺

Example 43: Synthesis of N1-3-pyridin-N5-(3-trifluoromethyl)benzylbiguanide hydrochloride

The target compound was obtained as a white solid (0.05 g, 8.0%) in thesame manner as in Example 1, except that 3-pyridinecyanoguanidine and3-trifluoromethylbenzylamine were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ9.01 (m, H), 8.87 (s, 1H), 8.49 (m, 2H), 8.08(m, 1H), 7.65 (3H), 4.69 (m, 2H)

LCMS: 337.2 [M+H]⁺

Example 44: Synthesis of N1-(3-methyl)piperidin-N5-cyclopentyl biguanidehydrochloride

The target compound was obtained as a white solid (0.05 g, 14.6%) in thesame manner as in Example 1, except that3-methylpiperidinecyanoguanidine and cyclopentylamine were used insteadof N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (400 Hz, CD₃OD) δ4.05 (m, 4H), 2.96 (m, 1H), 2.68 (m, 1H), 1.98(m, 3H), 1.65 (m, 9H), 1.32 (m, 1H), 0.95 (m, 4H)

LCMS: 252.2 [M+H]⁺

Example 45: Synthesis of N1-(3-methyl)piperidin-N5-(4-methoxy)piperidinebiguanide hydrochloride

The target compound was obtained as a white solid (0.03 g, 8.5%) in thesame manner as in Example 1, except that3-methylpiperidinecyanoguanidine and 4-methoxypiperidine were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ3.96 (m, 2H), 3.75 (m, 2H), 3.48 (m, 1H), 3.34(s, 3H), 3.30 (m, 1H), 2.80 (m, 1H), 2.59 (m, 1H), 1.88 (m, 3H), 1.66(m, 2H), 1.58 (m, 3H), 1.23 (m, 1H), 0.95 (d, 3H)

LCMS: 282.2 [M+H]⁺

Example 46: Synthesis of N1-(3-methyl)piperidin-N5-(4-ethoxy)piperidinebiguanide hydrochloride

The target compound was obtained as a white solid (0.04 g, 12.2%) in thesame manner as in Example 1, except that3-methylpiperidinecyanoguanidine and 4-ethoxypiperidine were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ4.01 (m, 2H), 3.82 (m, 2H), 3.58 (m, 4H), 3.31(m, 4H), 2.80 (m, 1H), 2.58 (m, 1H), 2.01 (m, 3H), 1.56 (m, 5H), 1.28(m, 1H), 0.95 (d, 3H)

LCMS: 292.2 [M+H]⁺

Example 47: Synthesis of N1-(3-methyl)piperidin-N5-pyrazin-2-ylbiguanide hydrochloride

The target compound was obtained as a white solid (0.01 g, 4.7%) in thesame manner as in Example 1, except that3-methylpiperidinecyanoguanidine and pyrazin-2-amine were used insteadof N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ8.48 (s, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 3.73(m, 2H), 3.12 (m, 1H), 2.75 (m, 1H), 1.80 (m, 4H), 1.23 (m, 1H), 0.92(d, 3H)

LCMS: 262.1 [M+H]⁺

Example 48: Synthesis of N1-(4-methyl)piperidin-N5-(4-bromo)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.32 g, 49.3%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 4-bromoaniline were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.45 (m, 2H), 7.30 (m, 2H), 4.07 (s, 2H), 2.99(t, 2H), 1.72 (m, 2H), 1.68 (m, 1H), 1.19 (m, 2H), 0.98 (d, 3H)

LCMS: 338.0, 340.2 [M, M+2]⁺

Example 49: Synthesis ofN1-4-methyl)piperidin-N5-(3-trifluoromethoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.49 g, 71.9%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 3-trifluoromethoxyaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.53 (s, 1H), 7.37 (t, 1H), 7.26 (m, 1H), 6.97(m, 1H), 4.07 (s, 2H), 3.02 (t, 2H), 1.74 (m, 2H), 1.70 (m, 1H), 1.23(m, 2H), 1.00 (d, 3H)

LCMS: 344.2 [M+H]⁺

Example 50: Synthesis ofN1-(4-methyl)piperidin-N5-(3-trifluoromethyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.50 g, 77.0%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 3-trifluoromethylaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.84 (s, 1H), 7.55 (d, 1H), 7.48 (t, 1H), 7.31(d, 1H), 4.07 (s, 2H), 3.02 (t, 2H), 1.76 (m, 2H), 1.70 (m, 1H), 1.23(m, 2H), 0.99 (d, 3H)

LCMS: 328.2 [M+H]⁺

Example 51: Synthesis ofN1-(3-methyl)piperidin-N5-(3-trifluoromethyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.49 g, 75.4%) in thesame manner as in Example 1, except that3-methylpiperidinecyanoguanidine and 3-trifluoromethylaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.86 (s, 1H), 7.55 (d, 1H), 7.48 (t, 1H), 7.31(d, 1H), 3.97 (s, 2H), 3.01 (t, 1H), 2.71 (t, 1H), 1.89 (m, 1H), 1.77(m, 1H), 1.70 (m, 1H), 1.59 (m, 1H), 1.23 (m, 1H), 0.94 (d, 3H)

LCMS: 328.2 [M+H]⁺

Example 52: Synthesis ofN-(4-methyl)piperidin-N5-(4-trifluoromethoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.68 g, 60.0%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 4-trifluoromethoxyaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.45 (d, 2H), 7.23 (d, 2H), 4.07 (d, 2H), 2.99(t, 2H), 1.75 (d, 2H), 1.69 (m, 1H), 1.21 (m, 2H), 0.99 (d, 3H)

LCMS: 344.2 [M+H]⁺

Example 53: Synthesis ofN1-(4-methyl)piperidin-N5-(4-trifluoromethyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.66 g, 61.0%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 4-trifluoromethylaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.58 (s, 4H), 4.06 (s, 2H), 3.04 (t, 2H), 1.76(m, 2H), 1.70 (m, 1H), 1.23 (m, 2H), 1.00 (d, 3H)

LCMS: 328.2 [M+H]⁺

Example 54: Synthesis ofN1-(4-methyl)piperidin-N5-(3-trifluoromethyl-4-fluoro)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.76 g, 66.7%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 3-trifluoromethyl-4-fluoroanilinewere used instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.83 (d, 1H), 7.58 (m, 1H), 7.28 (t, 1H), 3.01(t, 2H), 1.75 (m, 2H), 1.56 (m, 1H), 1.21 (m, 2H), 0.99 (d, 3H)

LCMS: 3.46.2 [M+H]⁺

Example 55: Synthesis of N1-(4-methyl)piperidin-N5-(4-chloro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.30 g, 50.3%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 4-chloroaniline were used insteadof N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃3OD) δ7.36 (d, 2H), 7.31 (d, 2H), 4.07 (d, 2H), 2.99(t, 2H), 1.75 (m, 2H), 1.69 (m, 1H), 1.21 (m, 2H), 0.99 (d, 3H)

LCMS: 294.2 [M+H]⁺

Example 56: Synthesis of N1-(4-methyl)piperidin-N5-(4-fluoro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.44 g, 7.1%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 4-fluoroaniline were used insteadof N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.35 (m, 2H), 7.06 (m, 2H), 4.07 (d, 2H), 2.97(t, 2H), 1.74 (d, 2H), 1.67 (m, 1H), 1.98 (m, 2H), 0.99 (d, 3H)

LCMS: 278.2 [M+H]⁺

Example 57: Synthesis ofN-(4-methyl)piperidin-N5-(3-fluoro-4-trifluoromethyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.29 g, 42.7%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 3-fluoro-4-trifluoromethylanilinewere used instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.62 (m, 2H), 7.24 (d, 2H), 4.07 (s, 2H), 3.06(s, 2H), 1.78 (d, 2H), 1.72 (m, 1H), 1.26 (d, 2H), 0.98 (d, 3H)

LCMS: 346.2 [M+H]⁺

Example 58: Synthesis ofN1-(4-methyl)piperidin-N5-(3-trifluoromethyl-4-chloro)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.50 g, 70.1%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 3-trifluoromethyl-4-chloroanilinewere used instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.95 (s, 1H), 7.53 (q, 2H), 4.07 (s, 2H), 3.04(t, 2H), 1.76 (m, 2H), 1.72 (m, 1H), 1.24 (m, 2H), 1.00 (d, 3H)

LCMS: 362.2 [M+H]⁺

Example 59: Synthesis ofN1-(4-methyl)piperidin-N5-(3-fluoro-4-trifluoromethoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.35 g, 49.7%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 3-fluoro-4-trifluoromethoxyanilinewere used instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.56 (d, 1H), 7.33 (t, 1H), 7.15 (d, 1H), 4.06(s, 2H), 3.03 (t, 2H), 1.77 (d, 2H), 1.70 (m, 1H), 1.24 (m, 2H), 1.00(d, 3H)

LCMS: 362.2 [M+H]⁺

Example 60: Synthesis ofN1-(4-methyl)piperidin-N5-(3-trifluoromethyl)benzyl biguanidehydrochloride

The target compound was obtained as a white solid (0.11 g, 17.2%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 3-trifluoromethylbenzylamine wereused instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.63 (s, 1H), 7.54 (m, 3H), 4.46 (s, 2H), 3.95(d, 2H), 2.88 (t, 2H), 1.67 (m, 3H), 1.13 (m, 2H), 0.95 (d, 3H)

LCMS: 342.2 [M+H]⁺

Example 61: Synthesis ofN-(4-methyl)piperidin-N5-(4-trifluoromethyl)benzyl biguanidehydrochloride

The target compound was obtained as a white solid (0.07 g, 10.8%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 4-trifluoromethyl benzylamine wereused instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.64 (d, 2H), 7.51 (d, 2H), 4.47 (s, 2H), 3.98(d, 2H), 2.89 (t, 2H), 1.65 (m, 3H), 1.10 (m, 2H), 0.94 (d, 3H)

LCMS: 342.2 [M+H]⁺

Example 62: Synthesis ofN1-(3,5-dimethyl)piperidin-N5-(4-trifluoromethoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.21 g, 30.0%) in thesame manner as in Example 1, except that3,5-dimethylpiperidinecyanoguanidine and 4-trifluoromethoxyaniline wereused instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, DMSO-d₆) δ7.77 (s, 2H), 7.49 (m, 2H), 7.30 (m, 2H), 6.98(s, 2H), 3.95 (d, 2H), 2.48 (t, 2H), 1.77 (d, 1H), 1.64 (s, 2H), 0.88(s, 6H), 0.87 (m, 1H)

LCMS: 358.2 [M+H]⁺

Example 63: Synthesis ofN1-(3,5-dimethyl)piperidin-N5-(4-trifluoromethyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.25 g, 31.2%) in thesame manner as in Example 1, except that 3,5-dimethylpiperidinecyanoguanidine and 4-trifluoromethylaniline were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, CD₃OD) δ 8.90 (m, 1H), 8.56 (m, 1H), 8.43 (m, 1H), 8.39(m, 1H), 7.91 (m, 1H), 7.76 (m, 2H), 7.41 (m, 1H)

LC-MS m/z 339.2 [M+1]⁺

Example 64: Synthesis of N1-(3,5-dimethyl)piperidin-N5-(4-fluoro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.30 g, 29.8%) in thesame manner as in Example 1, except that3,5-dimethylpiperidinecyanoguanidine and 4-fluoroaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, DMSO-d₆) δ 7.69 (s, 1H), 7.45 (m, 1H), 7.39 (m, 2H),7.32 (m, 1H), 6.95 (s, 1H), 3.95 (d, 2H), 2.40 (t, 2H), 1.68 (d, 1H),1.62 (s, 2H), 0.88 (s, 6H), 089 (m, 1H)

LCMS: 292.2 [M+H]⁺

Example 65: Synthesis ofN1-(3,5-dimethyl)piperidin-N5-(3-trifluoromethyl-4-fluoro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.15 g, 15.0%) in thesame manner as in Example 1, except that3,5-dimethylpiperidinecyanoguanidine and3-trifluoromethyl-4-fluoroaniline were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz; DMSO-d₆) δ 7.89 (m, 1H), 7.80 (s, 1H), 7.65 (m, 1H),7.44 (m, 1H), 7.04 (m, 1H), 3.98 (d, 2H), 2.43 (m, 2H), 1.77 (d, 1H),1.62 (s, 2H), 0.83 (s, 6H), 0.84 (m, 1H)

LCMS: [M+H]⁺

Example 66: Synthesis of N1-2,5-dihydro-1H-pyrrol-N5-pyridin-3-ylbiguanide hydrochloride

The target compound was obtained as a white solid (0.18 g, 31.3%) in thesame manner as in Example 1, except that2,5-dihydro-1H-pyrrolecyanoguanidine and pyrazin-2-amine were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ8.57 (s, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.36(s, 1H), 5.91 (s, 2H), 4.24 (d, 4H)

LCMS: 231.2 [M+H]⁺

Example 67: Synthesis ofN1-2,5-dihydro-1H-pyrrol-N5-2,5-dihydro-1H-pyrrole biguanidehydrochloride

The target compound was obtained as a white solid (0.40 g, 28.8%) in thesame manner as in Example 1, except that2,5-dihydro-1H-pyrrolecyanoguanidine and 2,5-dihydro-1H-pyrrole wereused instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ5.99 (s, 4H), 4.39 (m, 8H)

LCMS: 206.2 [M+H]⁺

Example 68: Synthesis ofN1-1,2,3,6-tetrahydropyridin-N5-1,2,3,6-tetrahydropyridine biguanidehydrochloride

The target compound was obtained as a white solid (0.59 g, 16.3%) in thesame manner as in Example 1, except that1,2,3,6-tetrahydropyridinecyanoguanidine and 1,2,3,6-tetrahydropyridinewere used instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz. CD₃OD) δ5.97 (s, 2H), 5.75 (d, 2H), 3.98 (s, 4H), 2.25(s, 4H)

LCMS: 234.2 [M+H]⁺

Example 69: Synthesis of N1-(4-methyl)piperidin-N-(4-aminoethyl)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.06 g, 16.9%) in thesame manner as in Example 1, except that4-methylpiperidinecyanoguanidine and 4-aminoethylaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.37 (d, 2H), 7.25 (d, 2H), 4.09 (d, 2H), 3.2(m, 2H), 3.01 (m, 4H), 1.75 (m, 3H), 1.21 (m, 2H), 0.98 (m, 3H)

LCMS: 303.2 [M+H]⁺

Example 70: Synthesis of N1-pyrrolidin-N5-(4-acetyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.49 g, 44.1%) in thesame manner as in Example 1, except that pyrrolidinecyanoguanidine and4-acetylaniline were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (600 Hz, CD₃OD) δ7.95 (d, 2H), 7.56 (d, 2H), 3.31 (d, 4H), 2.56(s, 3H), 2.10 (d, 4H)

LCMS: 274.2 [M+H]⁺

Example 71: Synthesis of N1-piperidin-N5-(4-morpholin-4-yl)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.93 g, 69.1%) in thesame manner as in Example 1, except that piperidinecyanoguanidine and4-morpholin-4-ylaniline were used instead of N,N-dimethylcyanoguanidineand piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.22 (d, 2H), 6.96 (d, 2H), 3.83 (m, 4H), 3.50(m, 4H), 3.12 (m, 4H), 1.69 (m, 2H), 1.63 (s, 4H)

LCMS: 331.2 [M+H]⁺

Example 72: Synthesis of N1-pyrrolidin-N5-(4-bromo)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.91 g, 73.2%) in thesame manner as in Example 1, except that pyrrolidinecyanoguanidine and4-bromoaniline were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (600 Hz, CD₃OD) δ7.43 (d, 2H), 7.35 (d, 2H), 3.48 (d, 4H), 2.06(d, 4H)

LCMS: 310.0, 312.0 [M, M+2]⁺

Example 73: Synthesis of N-piperidin-N5-(4-methoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.31 g, 30.4%) in thesame manner as in Example 1, except that piperidinecyanoguanidine and4-methoxyaniline were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (600 Hz, CD₃OD) δ7.24 (d, 2H), 6.91 (d, 2H), 3.78 (s, 3), 3.50(s, 4H), 1.69 (m, 2H), 1.62 (s, 4H)

LCMS: 276.2 [M+H]⁺

Example 74: Synthesis of N1-piperidin-N5-(2-propyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.67 g, 63.6%) in thesame manner as in Example 1, except that piperidinecyanoguanidine and2-propylaniline were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (600 Hz, CD₃OD) δ7.31 (m, 1H), 7.27 (m, 1H), 7.21 (m, 2H), 3.47(m, 4H), 2.65 (t, 2H), 1.63 (m, 8H), 0.97 (m, 3H)

LCMS: 288.2 [M+H]⁺

Example 75: Synthesis of N1-pyrrolidin-N5-(2-trifluoromethyl)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.53 g, 44.4%) in thesame manner as in Example 1, except that pyrrolidinecyanoguanidine and2-trifluoromethylaniline were used instead of N,N-dimethylcyanoguanidineand piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.70 (m, 3H), 7.60 (s, 1H), 3.04 (d, 4H), 2.08(d, 4H)

LCMS: 300.2 [M+H]⁺

Example 76: Synthesis ofN1-pyrrolidin-N5-(2-chloro-5-trifluoromethyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.36 g, 32.3%) in thesame manner as in Example 1, except that pyrrolidinecyanoguanidine and2-chloro-5-trifluoromethylaniline were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.58 (s, 1H), 7.32 (m, 2H), 3.24 (d, 4H), 2.21(d, 4H)

LCMS: 334.2 [M+H]⁺

Example 77: Synthesis of N1-pyrrolidin-N5-(3-chloro-4-fluoro)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.72 g, 54.3%) in thesame manner as in Example 1, except that pyrrolidinecyanoguanidine and3-chloro-4-fluoroaniline were used instead of N,N-dimethylcyanoguanidineand piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.64 (m, 1H), 7.29 (m, 1H), 7.21 (m, 1H), 3.49(d, 4H), 2.07 (d, 4H)

LCMS: 284.2 [M+H]⁺

Example 78: Synthesis of N1-pyrrolidin-N5-(2,3-dichloro)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.74 g, 60.8%) in thesame manner as in Example 1, except that pyrrolidinecyanoguanidine and2,3-dichloroaniline were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (600 Hz, CD₃OD) δ7.77 (m, 1H), 7.22 (m, 1H), 7.25 (m, 1H), 3.46(d, 4H), 2.05 (4H)

LCMS: 300.1 [M+H]⁺

Example 79: Synthesis of N1-pyrrolidin-N5-(4-trifluoromethylthio)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.94 g, 71.2%) in thesame manner as in Example 1, except that pyrrolidinecyanoguanidine and4-trifluoromethylthioaniline were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.59 (m, 4H), 3.52 (d, 4H), 2.08 (d, 4H)

LCMS: 332.2 [M+H]⁺

Example 80: Synthesis of N1-pyrrolidin-N5-(2,6-difluoro)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.09 g, 48.0%) in thesame manner as in Example 1, except that pyrrolidinecyanoguanidine and2,6-difluoroaniline were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (600 MHz, DMSO-d₆) δ7.47 (s, 2H), 7.34 (m, 1H), 7.14 (t, 2H),7.01 (s, 2H) 3.27 (d, 4H), 1.94 (d, 4H)

LCMS: 268.2 [M+H]⁺

Example 81: Synthesis of(3-(3-(imino(piperidin-1-yl)methyl)guanidino)benzyl)triphenylphosphonium chloride

The target compound was obtained as a white solid (0.01 g, 5.0%) in thesame manner as in Example 1, except that piperidinecanoguanidine and(3-aminobenzyl)triphenylphosphonium chloride were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (400 MHz, DMSO-d₆) δ7.82 (m, 6H), 7.77 (m, 3H), 7.50 (m, 6H),7.38 (m, 2H), 7.17 (m, 1H), 4.65 (s, 2H), 3.11 (t, 4H), 1.30 (m, 4H)

LCMS: 554.2 [M+H]⁺

Example 82: Synthesis ofN1-pyrrolidin-N5-methyl-N5-(4-trifluoromethoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (1.32 g, 76.7%) in thesame manner as in Example 1, except that pyrrolidinecyanoguanidine andN-methyl-4-trifluoromethoxyaniline were used instead ofN,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz, CD₃OD) δ7.41 (d, 2H), 7.20 (d, 2H), 3.20 (d, 4H), 2.84(s, 3H), 1.98 (d, 4H)

LCMS: 330.1 [M+H]⁺

Example 83: Synthesis of N1-pyrrolidin-N5-(4-phenoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.09 g, 8.3%) in thesame manner as in Example 1, except that pyrrolidinecyanoguanidine and4-phenoxyaniline were used instead of N,N-dimethylcyanoguanidine andpiperidine.

¹H NMR (400 MHz, CD₃OD) δ7.31 (m, 4H), 7.03 (m, 1H), 6.89 (m, 4H), 3.43(d, 4H), 1.98 (d, 4H)

LCMS: 324.2 [M+H]⁺

Example 84: Synthesis of N1,N1-dimethyl-N5-(4-trifluoromethoxy)phenylbiguanide hydrochloride

The target compound was obtained as a white solid (0.30 g, 34.5%) in thesame manner as in Example 1, except that 4-trifluoromethoxyaniline wasused instead of piperidine.

¹H NMR (600 MHz, DMSO) δ7.41 (d, J=8 Hz, 2H), 7.20 (d, J=8 Hz, 2H), 3.20(s, 6H)

LCMS: 290.1 [M+H]⁺

Example 85: Synthesis ofN1,N1-dimethyl-N5-methyl-N5-(4-trifluoromethoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.70 g, 77.0%) in thesame manner as in Example 1, except thatN-methyl-4-trifluoromethoxyaniline was used instead of piperidine.

¹H NMR (600 MHz, DMSO) δ7.39 (d, J=8 Hz, 2H), 7.18 (d, J=8 Hz, 2H), 3.23(s, 6H), 2.86 (s, 3H)

LCMS: 304.2 [M+H]⁺

Example 86: Synthesis ofN1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N5-thiophenethyl biguanidehydrochloride

The target compound was obtained as a white solid (0.09 g, 10.0%) in thesame manner as in Example 1, except that2-(benzo[d][1,3]dioxol-5-yl)ethylcyanoguanidine and thiophenethyl wereused instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ6.91 (m, 3H), 6.70 (m, 3H), 5.83 (s, 2H), 3.10(m, 4H), 2.99 (m, 2H), 2.70 (m, 2H)

LCMS: 360.1 [M+H]⁺

Example 87: Synthesis ofN1-(N-acetyl)piperazin-N5-(4-trifluoromethoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.40 g, 40.6%) in thesame manner as in Example 1, except thatN-acetylpiperazinecyanoguanidine and 4-trifluoromethoxyaniline were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 MHz. CD₃OD) δ7.47 (d, 2H), 7.23 (d, 2H), 3.69 (m, 3H), 3.79(m, 4H), 2.13 (s, 4H)

LCMS: 373.1 [M+H]⁺

Example 88: Synthesis of N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N5-butylbiguanide hydrochloride

The target compound was obtained as a white solid (0.01 g, 22.0%) in thesame manner as in Example 1, except that2-(benzo[d][1,3]dioxol-5-yl)ethylcyanoguanidine and 1-butylamine wereused instead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ6.70 (m, 3H), 5.83 (s, 2H), 3.10 (t, 4H), 2.99(m, 2H), 2.70 (t, 2H), 1.5 (m, 2H), 0.99 (m, 3H)

LCMS: 306.2 [M+H]⁺

Example 89: Synthesis ofN1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N5-phenethyl biguanidehydrochloride

The target compound was obtained as a white solid (0.50 g, 28.0%) in thesame manner as in Example 1, except that2-(benzo[d][1,3]dioxol-5-yl)ethylcyanoguanidine and phenethyl were usedinstead of N,N-dimethylcyanoguanidine and piperidine.

¹H NMR (600 Hz, CD₃OD) δ7.21 (m, 5H), 6.78 (m, 3H), 5.99 (s, 2H), 3.13(t, 4H), 2.99 (m, 2H), 2.87 (t, 2H)

LCMS: 354.2 [M+H]⁺

Example 90: Synthesis ofN1-(4,4-difluoro)piperidin-N5-(3,4-dichloro)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.20 g, 50.0%) in thesame manner as in Example 1, except that 4,4-difluoropiperidinecyanoguanidine and 3,4-dichloroaniline were used instead ofN,N-dimethylcyanoguanidine and piperidine.

Example 91: Synthesis ofN1-(4,4-difluoro)piperidin-N5-(5,6,7,8-tetrahydronaphthalene) biguanidehydrochloride

The target compound was obtained as a white solid (0.30 g, 60.0%) in thesame manner as in Example 1, except that4,4-difluoropiperidinecyanoguanidine and5,6,7,8-tetrahydronaphthalen-2-amine were used instead ofN,N-dimethylcyanoguanidine and piperidine.

Example 92: Synthesis of N1-butyl-N2-cycloheptyl biguanide hydrochloride

1-Butyl-3-cycloheptylthiourea (4.1 g, 18.0 mmol) was dissolved inethanol (150 mL) at room temperature. Mercury oxide (7.8 g, 30.1 mmol)and guanidine hydrochloride (5.1 g, 54.0 mmol) were added thereto andthe mixture was stirred under reflux for 15 hours. The reaction mixturewas filtered, concentrated under reduced pressure, and separated andpurified using a chromatography in a condition where the ratio ofmethylene chloride to methyl alcohol was 9:1 and the target compound wasobtained as a white solid (2.00 g, 38.0%).

¹H NMR (600 MHz, DMSO) δ3.55 (m, 1H), 3.01 (m, 2H), 1.77 (m, 2H), 1.58(s, 2H), 1.49 (m, 8H), 1.37 (m, 2H), 1.28 (m, 2H), 0.84 (m, 3H)

LCMS: 254.4 [M+H]⁺

Example 93: Synthesis ofN1,N1-dimethyl-N2-(4-fluoro)benzyl-N5-piperidine biguanide hydrochloride

The target compound was obtained as a white solid (0.15 g, 42.3%) in thesame manner as in Example 92, except that1-(1,1-dimethyl)-3-(4-fluoro)benzylthiourea and piperidineguanidine wereused instead of 1-butyl-3-cycloheptylthiourea and guanidinehydrochloride.

¹H NMR (600 MHz, CDCl₃) δ7.34 (m, 1H), 6.96 (m, 2H), 3.57 (s, 2H), 2.84(m, 6H), 1.64 (m, 4H), 1.42 (m, 4H), 1.19 (m, 2H)

LCMS: 306.1 [M+H]⁺

Example 94: Synthesis of N1-phenyl-N2-phenethyl biguanide hydrochloride

The target compound was obtained as a white solid (0.02 g, 2.0%) in thesame manner as in Example 92, except that 1-phenyl-3-phenethylthioureawas used instead of 1-butyl-3-cycloheptylthiourea.

¹H NMR (600 MHz, DMSO) δ7.32 (m, 7H), 7.17 (d, J=8.4 Hz, 2H), 7.17 (t,J=8.4 Hz, 1H), 3.38 (m, 2H), 2.86 (t, J=7.2 Hz, 2H)

LCMS: 282.1 [M+H]⁺

Example 95: Synthesis of N1-phenethyl-N2-(4-bromo)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.15 g, 31.5%) in thesame manner as in Example 92, except that1-phenethyl-3-(4-bromo)phenylthiourea was used instead of1-butyl-3-cycloheptylthiourea.

¹H NMR (400 MHz, DMSO) δ8.01 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.46 (d,J=7.6 Hz, 1H), 7.32 (t, J=7.6 Hz, 2H), 7.23 (m, 3H), 7.14 (t, J=7.6 Hz,1H), 3.44 (m, 2H), 2.77 (t, J=7.2 Hz, 2H)

LCMS: 360.0 [M+H]⁺

Example 96: Synthesis of N1-benzyl-N2-methyl-N5N5-dimethyl biguanidehydrochloride

The target compound was obtained as a white solid (0.03 g, 2.0%) in thesame manner as in Example 92, except that 1-benzyl-3-methylthiourea andN,N-dimethylguanidine were used instead of 1-butyl-3-cycloheptylthioureaand guanidine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.35 (d, J=7.2 Hz, 2H), 7.29 (t, J=7.2 Hz, 2H),7.20 (t, J=7.2 Hz, 1H), 4.52 (s, 2H), 3.45 (s, 3H), 3.29 (s, 3H), 2.97(s, 6H)

LCMS: 234.1 [M+H]⁺

Example 97: Synthesis of N1-phenethyl-N2-methyl-N5,N5-dimethyl biguanidehydrochloride

The target compound was obtained as a white solid (0.35 g, 24.8%) in thesame manner as in Example 92, except that 1-phenethyl-3-methylthioureaand N,N-dimethylguanidine were used instead of1-butyl-3-cycloheptylthiourea and guanidine hydrochloride.

¹H NMR (600 MHz, CD₃OD) δ7.28 (m, 2H), 7.20 (m, 3H), 3.53 (m, 2H), 3.30(m, 8H), 3.13 (s, 3H)

LCMS: 248.1 [M+H]⁺

Example 98: Synthesis of N1-(4-chloro)benzyl-N2-cycloheptyl biguanidehydrochloride

The target compound was obtained as a white solid (0.18 g, 27.0%) in thesame manner as in Example 92, except that1-(4-chloro)benzyl-3-cycloheptylthiourea was used instead of1-butyl-3-cycloheptylthiourea.

¹H NMR (400 MHz, DMSO) δ 7.37 (q, J=7.2 Hz, 4H), 4.26 (s, 2H), 3.53 (m,1H), 1.48 (m, 12H)

LCMS: 322.2 [M+H]⁺

Example 99: Synthesis of N1-piperidin-N2-(2-thiophen-2-yl)ethylbiguanide hydrochloride

The target compound was obtained as a white solid (0.06 g, 22.0%) in thesame manner as in Example 92, except that1-piperidin-3-thiophenethylthiourea was used instead of1-butyl-3-cycloheptylthiourea.

¹H NMR (600 MHz, DMSO) δ7.36 (d, J=7.8 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H),6.89 (m, 1H), 3.29 (m, 4H), 3.04 (m, 4H), 1.57 (m, 6H)

LCMS: 280.2 [M+H]⁺

Example 100: Synthesis of N1-(benzo[d][1,3]dioxol-5-yl)methyl-N2-ethylbiguanide hydrochloride

The target compound was obtained as a white solid (0.33 g, 34.0%) in thesame manner as in Example 92, except that1-(benzo[d][1,3]dioxol-5-yl)methyl-3-ethylthiourea was used instead of1-butyl-3-cycloheptylthiourea

¹H NMR (600 MHz, DMSO) δ6.91 (s, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.78 (m,1H), 5.99 (s, 2H), 3.11 (m, 2H), 1.09 (t, J=7.2 Hz, 3H)

LCMS: 264.1 [M+H]⁺

Example 101: Synthesis of N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N2-ethylbiguanide hydrochloride

The target compound was obtained as a white solid (0.17 g, 48.0%) in thesame manner as in Example 92, except that1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-3-ethylthiourea was used insteadof 1-butyl-3-cycloheptylthiourea.

¹H NMR (600 Hz, CD₃OD) δ 6.75 (m, 2H), 6.69 (m, 1H), 4.85 (s, 2H), 3.39(t, 2H), 3.20 (q, 2H), 2.77 (t, 2H), 1.15 (t, 3H)

LCMS: 278.1 [M+H]⁺

Example 102: Synthesis of N1-2-(benzo[d][1,3]dioxol-5-v)ethyl-N2-methylbiguanide hydrochloride

The target compound was obtained as a white solid (0.12 g, 30.1%) in thesame manner as in Example 92, except that1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-3-methylthiourea was used insteadof 1-butyl-3-cycloheptylthiourea.

¹H NMR (600 Hz, DMSO-d₆) δ6.79 (m, 2H), 6.64 (m, 1H), 5.91 (s, 2H), 3.24(s, 3H), 2.66 (s, 4H)

LCMS: 264.2 [M+H]⁺

Example 103: Synthesis of N1-(2-thiophen-2-yl)ethyl-N2-phenethylbiguanide hydrochloride

The target compound was obtained as a white solid (0.58 g, 95.1%) in thesame manner as in Example 92, except that1-thiophenethyl-3-phenethylthiourea was used instead of1-butyl-3-cycloheptylthiourea.

¹H NMR (600 Hz, CD₃OD) δ7.42 (m, 5H), 6.70 (m, 3H), 3.10 (m, 4H), 2.90(m, 4H)

LCMS: 360.1 [M+H]⁺

Example 104: Synthesis ofN1-(2-thiophen-2-yl)ethyl-N2-2-(benzo[d][1,3]dioxol-5-yl)ethyl biguanidehydrochloride

The target compound was obtained as a white solid (0.06 g, 26.7%) in thesame manner as in Example 92, except that1-thiophenethyl-3-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)thiourea was usedinstead of 1-butyl-3-cycloheptylthiourea.

¹H NMR (600 Hz, CD₃OD) δ7.01 (m, 1H), 6.98 (m, 2H), 6.70 (m, 3H), 5.83(s, 2H), 3.10 (m, 4H), 2.99 (m, 2H), 2.70 (m, 2H)

LCMS: 316.2 [M+H]⁺

Example 105: Synthesis ofN1-(4-trifluoromethoxy)phenyl-N2-methyl-N5-pyrrolidine biguanidehydrochloride

The target compound was obtained as a white solid (0.04 g, 8.6%) in thesame manner as in Example 92, except that1-(4-trifluoromethoxy)phenyl-3-methylthiourea and pyrrolidineguanidinewere used instead of 1-butyl-3-cycloheptylthiourea and guanidinehydrochloride.

¹H NMR (600 MHz, CD₃OD) δ7.32 (d, 2H), 7.25 (d, 2H), 3.20 (d, 4H), 2.98(s, 3H), 1.99 (d, 4H)

LCMS: 330.1 [M+H]⁺

Example 106: Synthesis ofN1-methyl-N1-(4-trifluoromethoxy)phenyl-N2-methyl-N5-pyrrolidinebiguanide hydrochloride

The target compound was obtained as a white solid (0.01 g, 5.6%) in thesame manner as in Example 92, except that1-(N-methyl-4-trifluoromethoxy)phenyl-3-methylthiourea andpyrrolidineguanidine were used instead of 1-butyl-3-cycloheptylthioureaand guanidine hydrochloride.

¹H NMR (600 MHz, CD₃OD) δ7.40 (d, 2H), 7.34 (d, 2H), 3.34 (s, 3H), 3.30(m, 4H), 3.20 (s, 3H), 1.86 (s, 4H)

LCMS: 344.1 [M+H]⁺

Example 107: Synthesis ofN1-(benzo[d][1,3]dioxol-5-yl)methyl-N2-cyclopentyl biguanidehydrochloride

The target compound was obtained as a white solid (0.65 g, 53.3%) in thesame manner as in Example 92, except that1-(benzo[d][1,3]dioxol-5-yl)methyl-3-cyclopentylthiourea was usedinstead of 1-butyl-3-cycloheptylthiourea.

¹H NMR (600 MHz, CD₃OD) δ6.93 (m, 1H), 6.88 (m, 1H), 6.83 (m, 1H), 5.98(s, 2H), 4.51 (s, 2H), 3.34 (s, 1H), 2.12 (s, 2H), 1.80 (s, 2H), 1.66(s, 4H)

LCMS: 304.4 [M+H]⁺

Example 108: Synthesis of N1-methyl biguanide hydrochloride

Methylamine hydrochloride (1.3 g, 19.84 mmol) was dissolved in n-butanol(30 mL) at room temperature. Cyanoguanidine (1.68 g, 19.98 mmol) wasadded thereto and the mixture was stirred under reflux for 15 hours. Thereaction mixture was concentrated under reduced pressure, and separatedand purified using a chromatography in a condition where the ratio ofmethylene chloride to methyl alcohol was 9:1 and the target compound wasobtained as a white solid (0.90 g, 61.0%).

¹H NMR (600 MHz, DMSO) δ2.86 (s, 3H)

LCMS: 116.1 [M+H]⁺

Example 109: Synthesis of N1-hexyl biguanide hydrochloride

The target compound was obtained as a white solid (0.60 g, 23.0%) in thesame manner as in Example 109, except that 1-hexylamine was used insteadof methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ3.24 (q, J=6.6 Hz, 2H), 1.52 (m, 2H), 1.31 (m,6H), 0.85 (t, J=6.6 Hz, 3H)

LCMS: 186.2 [M+H]⁺

Example 110: Synthesis of N1-(4-chloro)phenyl biguanide hydrochloride

The target compound was obtained as a white solid (0.75 g, 30.0%) in thesame manner as in Example 109, except that 4-chloroaniline was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.42 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H)

LCMS: 212.0 [M+H]⁺

Example 111: Synthesis of N1-2-prophene) biguanide hydrochloride

The target compound was obtained as a white solid (0.52 g, 24.0%) in thesame manner as in Example 109, except that 2-propenamine was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ5.75 (m, 1H), 5.17 (d, J=16.8 Hz, 2H), 3.70 (m,2H)

LCMS: 142.2 [M+H]⁺

Example 112: Synthesis of N1-(benzo[d][1,3]dioxol-5-yl)methyl biguanidehydrochloride

The target compound was obtained as a white solid (0.90 g, 18.4%) in thesame manner as in Example 109, except that(benzo[d][1,3]dioxol-5-yl)methanamine was used instead of methylaminehydrochloride.

¹H NMR (600 MHz, DMSO) δ7.00 (s, 1H), 6.68 (s, 2H), 5.97 (s, 2H), 4.36(s, 2H)

LCMS: 236.0 [M+H]⁺

Example 113: Synthesis of N1-phenyl biguanide hydrochloride

The target compound was obtained as a white solid (1.51 g, 71.4%) in thesame manner as in Example 109, except that aniline was used instead ofmethylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.33 (m, 2H), 7.25 (m, 2H), 6.99 (m, 1H)

LCMS: 178.2 [M+H]⁺

Example 114: Synthesis of N1-propyl biguanide hydrochloride

The target compound was obtained as a white solid (1.91 g, 53.3%) in thesame manner as in Example 109, except that 1-propylamine was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ3.01 (m, 2H), 1.43 (m, 2H), 0.84 (m, 3H)

LCMS: 144.3 [M+H]⁺

Example 115: Synthesis of N1,N1-diisopropyl biguanide hydrochloride

The target compound was obtained as a white solid (1.62 g, 36.6%) in thesame manner as in Example 109, except that N,N-diisopropylamine was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ3.27 (m, 2H), 1.19 (m, 12H)

LCMS: 186.2 [M+H]⁺

Example 116: Synthesis of N1-(4-bromo)phenyl biguanide hydrochloride

The target compound was obtained as a white solid (1.91 g, 74.6%) in thesame manner as in Example 109, except that 4-bromoaniline was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.45 (m, 2H), 7.35 (m, 2H)

LCMS: 257.1 [M+H]⁺

Example 117: Synthesis of N1-(4-acetyl)phenyl biguanide hydrochloride

The target compound was obtained as a white solid (0.61 g, 27.8%) in thesame manner as in Example 109, except that 4-acetylaniline was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz. DMSO) δ7.88 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H),2.50 (s, 3H)

LCMS: 220.2 [M+H]⁺

Example 118: Synthesis of N1-morpholin-4-yl biguanide hydrochloride

The target compound was obtained as a white solid (1.36 g, 79.5%) in thesame manner as in Example 109, except that morpholin-4-yl was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz. DMSO) δ3.58 (m, 4H), 3.43 (m, 4H)

LCMS: 172.1 [M+H]⁺

Example 119: Synthesis of N1-(2-trifluoromethyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.05 g, 2.0%) in thesame manner as in Example 109, except that 2-trifluoromethylaniline wasused instead of methylamine hydrochloride.

¹H NMR (400 MHz, DMSO) δ8.17 (s, 1H), 8.03 (d, J=8 Hz, 1H), 7.53 (t, J=8Hz, 2H), 7.79 (d, J=8 Hz, 1H)

LCMS: 246.0 [M+H]⁺

Example 120: Synthesis of N1-(4-methoxy)phenyl biguanide hydrochloride

The target compound was obtained as a white solid (1.85 g, 89.3%) in thesame manner as in Example 109, except that 4-methoxyaniline was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.23 (d, J=7.2 Hz, 2H), 6.87 (d, J=7.2 Hz, 2H),3.70 (s, 3H)

LCMS: 208.1 [M+H]⁺

Example 121: Synthesis of N1-(2-propyl)phenyl biguanide hydrochloride

The target compound was obtained as a white solid (0.75 g, 25.0%) in thesame manner as in Example 109, except that 2-propylaniline was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz. DMSO) δ7.16 (m, 4H), 2.59 (m, 2H), 1.55 (m, 2H), 0.93(m, 3H)

LCMS: 220.2 [M+H]⁺

Example 122: Synthesis of N-(4-morpholin-4-yl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.96 g, 36.6%) in thesame manner as in Example 109, except that 4-morpholin-4-ylaniline wasused instead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.18 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4 Hz), 3.71(m, 4H), 3.03 (m, 4H)

LCMS: 263.1 [M+H]⁺

Example 123: Synthesis of N1-piperidine biguanide hydrochloride

The target compound was obtained as a white solid (0.20 g, 8.0%) in thesame manner as in Example 109, except that piperidine was used insteadof methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ 3.42 (m, 4H), 1.57 (m, 2H), 1.49 (m, 4H)

LCMS: 170.2 [M+H]⁺

Example 124: Synthesis of N1-benzyl biguanide hydrochloride

The target compound was obtained as a white solid (0.70 g, 20.0%) in thesame manner as in Example 109, except that benzylamine was used insteadof methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.33 (m, 5H), 4.35 (d, J=6 Hz, 2H)

LCMS: 192.3 [M+H]⁺

Example 125: Synthesis of N1-4-(N-acetylamino)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (1.97 g, 61.0%) in thesame manner as in Example 109, except that 4-(N-acetylamino)aniline wasused instead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.46 (m, 2H), 6.97 (m, 2H), 1.97 (s, 3H)

LCMS: 235.0 [M+H]⁺

Example 126: Synthesis of N1-pyrrolidine biguanide hydrochloride

The target compound was obtained as a white solid (0.42 g, 27.0%) in thesame manner as in Example 109, except that pyrrolidine was used insteadof methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ3.31 (m, 4H), 1.87 (m, 4H)

LCMS: 156.2 [M+H]⁺

Example 127: Synthesis of N1-4-(pyridin-2-yl)piperazine biguanidehydrochloride

The target compound was obtained as a white solid (1.74 g, 51.0%) in thesame manner as in Example 109, except that 1-(pyridin-2-yl)piperazinewas used instead of methylamine hydrochloride.

¹H NMR (600 MHz, D₂O) δ7.95 (d, J=7.8 Hz 1H), 7.55 (t, J=7.8 Hz, 1H),6.76 (d, J=7.8 Hz, 1H), 6.69 (t, J=7.8 Hz, 1H), 3.54 (m, 4H), 3.43 (m,4H)

LCMS: 248.3 [M+H]⁺

Example 128: Synthesis of N1-(4-trifluoromethyl)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (1.27 g, 38.0%) in thesame manner as in Example 109, except that 4-trifluoromethylaniline wasused instead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.60 (q, J=8.4 Hz, 4H)

LCMS: 246.0 [M+H]⁺

Example 129: Synthesis of N1-(4-chloro)benzyl biguanide hydrochloride

The target compound was obtained as a white solid (0.39 g, 12.0%) in thesame manner as in Example 109, except that 4-chlorobenzylamine was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.41 (q, J=7.8 Hz, 4H), 4.36 (d, J=4.8 Hz, 2H)

LCMS: 226.0 [M+H]⁺

Example 130: Synthesis of N1,N1-dibenzyl biguanide hydrochloride

The target compound was obtained as a white solid (0.17 g, 4.0%) in thesame manner as in Example 109, except that N,N-dibenzylamine was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.35 (t, J=7.8 Hz, 4H), 7.30 (d, J=7.8 Hz, 2H),7.26 (d, J=7.8 Hz, 4H), 4.54 (s, 4H)

LCMS: 282.3 [M+H]⁺

Example 131: Synthesis of N1-(4-methoxy)benzyl biguanide hydrochloride

The target compound was obtained as a white solid (0.28 g, 9.0%) in thesame manner as in Example 109, except that 4-methoxybenzylamine was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.24 (d, J=7.8 Hz, 2H), 6.90 (d, J=7.8 Hz, 2H),4.29 (d, J=6 Hz, 2H)

LCMS: 220.0 [M+H]⁺

Example 132: Synthesis of N1-(4-fluoro)benzyl biguanide hydrochloride

The target compound was obtained as a white solid (0.17 g, 6.0%) in thesame manner as in Example 109, except that 4-fluorobenzylamine was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.36 (m, 2H), 7.17 (m, 2H), 4.32 (d, J=6 Hz, 2H)

LCMS: 210.0 [M+H]⁺

Example 133: Synthesis of N1,1l-dihexyl biguanide hydrochloride

The target compound was obtained as a white solid (0.73 g, 30.0%) in thesame manner as in Example 109, except that N,N-dihexylamine was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ2.82 (t, J=7.8 Hz, 4H), 1.58 (m, 4H), 1.29 (m,12H), 0.86 (t, J=7.8 Hz, 6H)

LCMS: 270.2 [M+H]⁺

Example 134: Synthesis of N1-methyl-N1-butyl biguanide hydrochloride

The target compound was obtained as a white solid (0.71 g, 34.3%) in thesame manner as in Example 109, except that N-methyl-N-butylamine wasused instead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ3.27 (t, J=7.2 Hz, 2H), 2.86 (s, 3H), 1.43 (m,2H), 1.22 (m, 2H), 0.84 (t, J=7.2 Hz, 3H)

LCMS: 172.1 [M+H]⁺

Example 135: Synthesis of N1-methyl-N1-cyclohexyl biguanidehydrochloride

The target compound was obtained as a white solid (0.08 g, 5.0%) in thesame manner as in Example 109, except that N-methyl-N-cyclohexylaminewas used instead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ2.46 (m, 1H), 1.70 (m, 2H), 1.53 (m, 3H), 1.42(m, 2H), 1.22 (m, 2H), 1.04 (m, 1H)

LCMS: 198.1 [M+H]⁺

Example 136: Synthesis of N1,N1-dicyclohexyl biguanide hydrochloride

The target compound was obtained as a white solid (2.32 g, 70.0%) in thesame manner as in Example 109, except that N,N-dicyclohexylamine wasused instead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ3.03 (m, 2H), 1.96 (m, 4H), 1.71 (m, 4H), 1.57(m, 2H), 1.26 (m, 8H), 1.05 (m, 2H)

LCMS: 266.1 [M+H]⁺

Example 137: Synthesis of N1-(4-chloro)phenethyl biguanide hydrochloride

The target compound was obtained as a white solid (0.37 g, 13.0%) in thesame manner as in Example 109, except that 4-chlorophenethylamine wasused instead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.37 (s, 4H), 3.47 (s, 2H), 2.85 (s, 2H)

LCMS: 240.1 [M+H]⁺

Example 138: Synthesis of N1-(4-hydroxy)phenethyl biguanidehydrochloride

The target compound was obtained as a white solid (0.15 g, 10.0/%) inthe same manner as in Example 109, except that 4-hydroxyphenethylaminewas used instead of methylamine hydrochloride.

¹H NMR (600 MHz. DMSO) δ7.07 (d, J=8.4 Hz, 2H), 6.71 (d, J=8.4 Hz, 2H),3.38 (s, 2H), 2.72 (s, 2H)

LCMS: 222.2 [M+H]⁺

Example 139: Synthesis of N1-azepane biguanide hydrochloride

The target compound was obtained as a white solid (0.18 g, 8.0%) in thesame manner as in Example 109, except that azepane was used instead ofmethylamine hydrochloride.

¹H NMR (400 MHz, DMSO) δ3.44 (m, 4H), 1.64 (m, 4H), 1.49 (m, 4H)

LCMS: 184.2 [M+H]⁺

Example 140: Synthesis of N1-(4-trifluoromethoxy)phenyl biguanidehydrochloride

The target compound was obtained as a white solid (0.06 g, 15.0%) in thesame manner as in Example 109, except that 4-trifluoromethoxyaniline wasused instead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.46 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H)

LCMS: 262.1 [M+H]⁺

Example 141: Synthesis of N1-4-trifluoromethyl)benzyl biguanidehydrochloride

The target compound was obtained as a white solid (0.02 g, 6.0%) in thesame manner as in Example 109, except that 4-trifluoromethylaniline wasused instead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.71 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H),4.49 (s, 2H)

LCMS: 260.0 [M+H]⁺

Example 142: Synthesis of N1-(4-trifluoromethoxy)benzyl biguanidehydrochloride

The target compound was obtained as a white solid (0.01 g, 6.0%) in thesame manner as in Example 109, except that 4-trifluoromethoxybenzylaminewas used instead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO) δ7.51 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H),4.39 (s, 2H)

LCMS: 276.1 [M+H]⁺

Example 143: Synthesis of N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl biguanidehydrochloride

The target compound was obtained as a white solid (0.03 g, 40.0%) in thesame manner as in Example 109, except that2-(benzo[d][1,3]dioxol-5-yl)ethanamine was used instead of methylaminehydrochloride.

¹H NMR (600 Hz, CD₃OD) δ 6.78 (m, 3H), 5.93 (s, 2H), 3.13 (t, 2H), 2.87(t, 2H)

LCMS: 250.1 [M+H]⁺

Example 144: Synthesis of N1-(furan-2-yl)methyl biguanide hydrochloride

The target compound was obtained as a white solid (7.70 g, 22.0%) in thesame manner as in Example 109, except that furan-2-ylmethanamine wasused instead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO-d₆) δ7.87 (m, 1H), 7.55 (s, 1H), 7.15 (m, 4H),6.35 (m, 1H), 4.32 (s, 2H)

LCMS: 182.0 [M+H]⁺

Example 145: Synthesis of N1-(2-thiophen-2-yl)ethyl biguanidehydrochloride

The target compound was obtained as a white solid (10.21 g, 35.0%) inthe same manner as in Example 109, except that thiophenethylamine wasused instead of methylamine hydrochloride.

¹H NMR (600 MHz, DMSO-d₆) δ9.73 (s, 1H), 9.28 (s, 2H), 8.62 (s, 3H),7.34 (m, 1H), 6.94 (m, 1H), 6.92 (m, 1H), 3.52 (s, 2H), 3.08 (s, 2H)

LCMS: 212.0 [M+H]⁺

Example 146: Synthesis of N1-(2-fluoro-4-hydroxy)benzyl biguanidehydrochloride

The target compound was obtained as a white solid (0.01 g, 12.2%) in thesame manner as in Example 109, except that 2-fluoro-4-hydroxybenzylaminewas used instead of methylamine hydrochloride.

¹H NMR (600 MHz, CD₃OD) δ7.19 (m, 1H), 6.58 (m, 1H), 6.50 (m, 1H), 4.34(s, 2H)

LCMS: 226.1 [M+H]⁺

Example 147: Synthesis of N1-(4-fluoro)phenylpropyl biguanidehydrochloride

The target compound was obtained as a white solid (0.01 g, 22.0%) in thesame manner as in Example 109, except that3-(4-fluorophenyl)propan-1-amine was used instead of methylaminehydrochloride.

¹H NMR (600 MHz, CD₃OD) δ7.23 (m, 2H), 7.01 (m, 2H), 3.18 (t, 2H), 2.68(t, 2H), 1.88 (q, 2H)

LCMS: 238.2 [M+H]⁺

Example 148: Synthesis of N1-(4-methoxy)phenylpropyl biguanidehydrochloride

The target compound was obtained as a white solid (0.09 g, 10.0%) in thesame manner as in Example 109, except that3-(4-methoxyphenyl)propan-1-amine was used instead of methylaminehydrochloride.

¹H NMR (600 MHz, CD₃OD) δ7.14 (d, 2H), 6.85 (d, 2H), 3.18 (s, 2H), 2.57(s, 2H), 2.50 (s, 3H), 1.98 (s, 2H)

LCMS: 250.1 [M+H]⁺

Example 149: Synthesis of N1-(2-iodo)benzyl biguanide hydrochloride

The target compound was obtained as a white solid (0.10 g, 33.0%) in thesame manner as in Example 109, except that 2-iodobenzylamine was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz, CD₃OD) δ7.88 (m, 1H), 7.43 (s, 1H), 7.40 (s, 1H), 7.06(s, 1H), 4.33 (s, 2H)

LCMS: 318.0 [M+H]⁺

Example 150: Synthesis of N1-(3-iodo)benzyl biguanide hydrochloride

The target compound was obtained as a white solid (0.11 g, 25.5%) in thesame manner as in Example 109, except that 3-iodobenzylamine was usedinstead of methylamine hydrochloride.

¹H NMR (600 MHz. CD₃OD) δ7.78 (s, 1H), 7.67 (s, 1H), 7.19 (s, 1H), 7.18(s, 1H), 4.45 (s, 2H)

LCMS: 318.0 [M+H]⁺

Example 151: Synthesis ofN-(6,6-dimethyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamidehydrochloride

Ethyl-3-amino-3-methylbutanoate hydrochloride (0.20 g, 1.12 mmol) wasdissolved in ethanol (20 mL) at room temperature. Piperidinecyanoguanidine (0.17 g, 1.12 mmol) was added thereto and stirred underreflux for 15 hours. The reaction mixture was concentrated under reducedpressure, and separated and purified using a chromatography in acondition where the ratio of methylene chloride to methyl alcohol was9:1 and the target compound was obtained as a white solid (0.32 g,10.0%).

¹H NMR (600 MHz, CD₃OD) δ3.16 (m, 4H), 2.51 (m, 2H), 1.58 (m, 6H), 1.29(s, 6H)

LCMS: 252.2 [M+H]⁺

Example 152: Synthesis of1-(6,6-dimethyl-4-oxo-1,4,5,6-tetrahydropyrimidin-3-yl)guanidinehydrochloride

The target compound was obtained as a white solid (0.02 g, 11.0%) in thesame manner as in Example 151, except that cyanoguanidine was usedinstead of piperidine cyanoguanidine.

¹H NMR (600 MHz, CD₃OD) δ2.51 (m, 2H), 1.29 (s, 6H)

LCMS: 184.2 [M+H]⁺

Example 153: Synthesis ofN-(1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamidehydrochloride

The target compound was obtained as a white solid (0.01 g, 6.0%) in thesame manner as in Example 151, except that piperidine-1-carbamimidoylcyanide and propan-1,3-diamine were used instead of piperidinecyanoguanidine and ethyl-3-amino-3-methylbutanoate hydrochloride.

¹H NMR (600 MHz, CD₃OD) δ3.15 (m, 4H), 3.04 (m, 4H), 1.73 (m, 4H), 1.64(m, 4H)

LCMS: 210.2 [M+H]⁺

Example 154: Synthesis ofN-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamidehydrochloride

The target compound was obtained as a white solid (0.01 g, 5.0%) in thesame manner as in Example 151, except that ethyl-3-aminobutanoatehydrochloride was used instead of ethyl-3-amino-3-methylbutanoatehydrochloride.

¹H NMR (600 MHz, CD₃OD) δ53.14 (m, 4H), 3.00 (m, 1H), 2.51 (m, 2H), 1.58(m, 6H), 1.29 (s, 3H)

LCMS: 238.1 [M+H]⁺

Example 155: Synthesis ofN-(5-methyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamidehydrochloride

The target compound was obtained as a white solid (0.01 g, 5.0%) in thesame manner as in Example 151, except thatethyl-3-amino-2-methylbutanoate hydrochloride was used instead ofethyl-3-amino-3-methylbutanoate hydrochloride.

¹H NMR (600 MHz. CD₃OD) δ3.13 (m, 4H), 3.01 (m, 2H), 2.50 (m, 1H), 1.58(m, 6H), 1.29 (s, 3H)

LCMS: 238.1 [M+H]⁺

Example 156: Synthesis ofN-(4-oxo-1,4,5,6-tetrahydropyrimidine-2-yl)piperidin-1-carboximidamidehydrochloride

The target compound was obtained as a white solid (0.04 g, 10.0%) in thesame manner as in Example 151, except that ethyl-3-aminopropanoatehydrochloride was used instead of ethyl-3-amino-3-methylbutanoatehydrochloride.

¹H NMR (600 MHz, CD₃OD) δ3.15 (m, 4H), 3.03 (m, 2H), 2.52 (m, 2H), 1.58(m, 6H)

LCMS: 224.2 [M+H]⁺

Example 157: Synthesis ofN-(6-cyclopropyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamidehydrochloride

The target compound was obtained as a white solid (0.12 g, 8.0%) in thesame manner as in Example 151, except thatethyl-3-amino-3-cyclopropylpropanoate hydrochloride was used instead ofethyl-3-amino-3-methylbutanoate hydrochloride.

¹H NMR (600 MHz, DMSO) δ3.73 (m, 1H), 3.48 (m, 4H), 2.76 (m, 1H), 2.43(m, 1H), 1.68 (m, 6H), 1.52 (m, 1H), 0.90 (m, 4H)

LCMS: 264.2 [M+H]⁺

Example 158: Synthesis ofN-(5-methyl-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamidehydrochloride

The target compound was obtained as a white solid (0.01 g, 3.0%) in thesame manner as in Example 151, except that piperidine-1-carbamimidoylcyanide and 2-methylpropan-1,3-diamine were used instead of piperidinecyanoguanidine and ethyl-3-amino-3-methylbutanoate hydrochloride.

¹H NMR (600 MHz; CD₃OD) δ3.49 (m, 8H), 1.67 (m, 6H), 1.59 (m, 1H), 0.98(m, 3H)

LCMS: 224.2 [M+H]⁺

Example 159: Synthesis ofN-(6-isopropyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamidehydrochloride

The target compound was obtained as a white solid (0.02 g, 3.0%) in thesame manner as in Example 151, except thatethyl-3-amino-4-methylpentanoate hydrochloride was used instead ofethyl-3-amino-3-methylbutanoate hydrochloride.

¹H NMR (600 MHz, CD₃OD) δ 3.72 (m, 1H), 3.49 (m, 4H), 2.74 (m, 1H), 2.41(m, 1H), 1.67 (m, 6H), 1.53 (m, 1H), 0.92 (m, 6H)

LCMS: 266.2 [M+H]⁺

Example 160: Synthesis ofl-(5-methyl-4-ozo-1,4,5,6-tetrahydropyrimidin-3-yl)guanidinehydrochloride

The target compound was obtained as a white solid (0.02 g, 4.0%) in thesame manner as in Example 151, except that cyanoguanidine andethyl-3-amino-2-methylbutanoate hydrochloride were used instead ofpiperidine cyanoguanidine and ethyl-3-amino-3-methylbutanoatehydrochloride.

¹H NMR (600 MHz, CD₃OD) δ3.02 (m, 2H), 2.52 (m, 1H), 1.29 (s, 3H)

LCMS: 170.2 [M+H]⁺

Example 161: Synthesis ofN-(6-isobutyl-4-oxo-1,4,5,6-tetrahydroprimidin-2-yl)piperidin-1-carboximidamidehydrochloride

The target compound was obtained as a white solid (0.10 g, 8.0%) in thesame manner as in Example 151, except thatethyl-3-amino-5-methylhexanoate hydrochloride was used instead ofethyl-3-amino-3-methylbutanoate hydrochloride.

¹H NMR (600 MHz, CD₃OD) δ3.72 (m, 1H), 3.49 (m, 4H), 2.74 (m, 1H), 2.41(m, 1H), 1.67 (m, 7H), 1.53 (m, 1H), 1.35 (m, 1H), 0.92 (m, 6H)

LCMS: 266.2 [M+H]⁺

Example 162: Synthesis ofN-(4-methyl-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamidehydrochloride

The target compound was obtained as a white solid (0.01 g, 2.0%) in thesame manner as in Example 151, except that piperidine-1-carbamimidoylcyanide and butan-1,3-diamine were used instead of piperidinecyanoguanidine and ethyl-3-amino-3-methylbutanoate hydrochloride.

¹H NMR (600 MHz, DMSO) δ3.43 (m, 7H), 1.65 (m, 6H), 1.56 (m, 2H), 0.99(m, 3H)

LCMS: 224.1 [M+H]⁺

Example 163: Synthesis ofN-(6-propyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamidehydrochloride

The target compound was obtained as a white solid (0.01 g, 2.0%) in thesame manner as in Example 151, except that ethyl-3-aminohexanoatehydrochloride was used instead of ethyl-3-amino-3-methylbutanoatehydrochloride.

¹H NMR (600 MHz, CD₃OD) δ3.73 (m, 1H), 3.50 (m 4H), 2.72 (m, 1H), 2.40(m, 1H), 1.68 (m, 8H), 1.50 (m, 1H), 1.33 (m, 1H), 0.95 (m, 3H)

LCMS: 266.2 [M+H]⁺

Example 164: Synthesis ofl-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrimidin-3-yl)guanidinehydrochloride

The target compound was obtained as a white solid (0.02 g, 4.0%) in thesame manner as in Example 151, except that cyanoguanidine andethyl-3-aminobutanoate hydrochloride were used instead of piperidinecyanoguanidine and ethyl-3-amino-3-methylbutanoate hydrochloride.

¹H NMR (600 MHz, CD₃OD) δ3.00 (m, 1H), 2.51 (m, 2H), 1.29 (s, 3H)

LCMS: 170.1 [M+H]⁺

Example 165: Synthesis ofN-(4-ethyl-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamidehydrochloride

The target compound was obtained as a white solid (0.01 g, 5.0%) in thesame manner as in Example 151, except that pentan-3,5-diamine was usedinstead of ethyl-3-amino-3-methylbutanoate hydrochloride.

¹H NMR (600 MHz, CD₃OD) δ3.45 (m, 7H), 1.66 (m, 6H), 1.58 (m, 2H), 1.36(m, 2H), 0.99 (m, 3H)

LCMS: 238.2 [M+H]⁺

TEST EXAMPLES

The compounds synthesized by the methods described in Examples wereevaluated with respect to the effect of inhibiting proliferation ofcancer cells according to the methods described in Test Examples below.

Test Example 1: Measurement of Inhibitory Effect Against Cancer CellProliferation

HCT116 cells (purchased from Korean Cell Line Bank (KCLB)) derived fromhuman colorectal cancer were used, and the effect of a biguanidederivative on the inhibition of cancer cell proliferation was confirmedby measuring the value of a concentration (cell growth inhibitionconcentration. IC₅₀) at which 50% of the cell growth was inhibited usinga 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenytetrazolium bromide (MTT)reagent.

HCT6 cells were placed in a 96-well plate and cultured in RPMI-1640medium containing 10% calf serum for 16 hours until each well had a cellcount of about 5000. Then, to obtain the IC₅₀ value of each compound,the 100 mM PBS stock compound was treated to the cell culture atconcentrations of 10 mM, 1 mM, 200 μM, 40 μM, 8 μM, 1.6 μM, 0.32 μM, and0.064 μM and then cultured for 48 hours; the 50 mM PBS. EtOH stockcompound was treated to the cell culture at concentrations of 1 mM, 200μM, 40 μM, 8 μM, 1.6 μM, 0.32 μM, and 0.064 μM and then cultured for 48hours; and the 50 mM DMSO stock compound was treated to the cell cultureat concentrations of 100 μM, 25 μM, 6.25 μM, 1.56 μM, 0.39 μM, 0.10 μM,and 0.02 μM and then cultured for 48 hours. To confirm the living cellsafter treatment with the compounds, MTT was added to each cell cultureand incubated for additional 2 hours. The formazane crystals thus formedwere dissolved using dimethyl sulfoxide (DMSO) and absorbance of thesolution was measured at 560 nm. After culturing for 48 hours, the ratioof a cell count cultured on a well plate not treated with the compoundsto a cell count on a well plate treated with the compounds synthesizedin Examples was indicated as cell viability (%) according to eachtreated concentration. A cell viability curve was plotted using the cellviability (%) and the values of the concentration (IC₅₀) of thecompounds, at which 509% of the growth was inhibited, were calculated toconfirm their inhibitory effect against cancer cell proliferation.

The compounds synthesized by the methods described in Examples of thepresent invention were evaluated with respect to their oxygenconsumption rates (OCR) and extracellular acidification rates (ECAR)according to the methods described in Test Example below.

Test Example 2: Measurement of Inhibitory Effect Against OxygenConsumption Rate (OCR) and Extracellular Acidification Rate (ECAR)

Since biguanide-based drugs exhibit an anticancer effect by inhibitingoxidative phosphorylation, the cellular metabolic actions such as oxygenconsumption rates (OCR), extracellular acidification rates (ECAR), etc.,of the above compounds are measured.

A549 cell line (purchased from ATCC-American Type Culture Collection(ATCC)), a lung cancer cell line, is treated with the compounds and OCRand ECAR of the cells are measured and thereby those compounds whichshow an improved effect compared to phenformin are selected.

The cells are plated on an XF96 cell culture plate containing RPMI1640medium at a concentration of 5×10³ cells and cultured in 37° C. 5% CO₂conditions to allow them to be attached thereto.

After 24 hours, the cells are treated with the drug at a concentrationof 10 μM for 2 hours, the existing medium is washed with a medium for XFanalysis (15 mM D-glucose, 15 mM sodium pyruvate, 4 mM L-glutamine. pH7.4) to remove the medium using a Prep station and treated again withthe drugs, and cultured in 37° C., non-CO₂ conditions in the Prepstation for 1 hour. While culturing in the Prep station, a sensorcartridge is calibrated for 1 hour and added into a plate containingcells, and OCR and ECAR analyses are performed.

The measured values of OCR and ECAR of the compounds are calculated withreference to the measured values of OCR and ECAR of the control groupwhich is set at 0% and the values of OCR and ECAR of phenformin, whichwas used as the reference drug, set at 100%, and those compounds whichshow an improved effect compared to those of phenformin are selected.From the primarily-selected compounds, those compounds which show animproved effect are treated at various concentrations (0 μM, 0.5 μM, 1μM, 5 μM, 10 μM, and 20 μM) and their reactivity according toconcentration was obtained.

The results of inhibitory effects of the compounds against cancer cellproliferation are shown in Table 1 below.

TABLE 1 OCR ECAR IC₅₀ (uM) @ AMPKa activation [pT172] (Unit/ml) @ MCF7cell (A549, 3 hrs) (A549, 3 hrs) Example HCT116 0 5 uM 10 uM 50 uM 10 uM10 uM 1 ND 5.3 4.6 2 ND 5.3 4.9 3 ND 5.3 6.2 4 ND 5.3 3.8 5 ND 5.3 5.8 6ND 5.3 4.8 16.7%  9.3% 7 >100 5.3 16.2 22.3 34.6 8 >100 4.4 10.8 12.519.3 9 ND 5.3 16.3 10 >100 6.8 10.4 11 4.8 4.6 cell death (8 htreatment) 12 >100 6.8 3.1 13 >100 6.8 7.0 −20.0%  61.0% 14 >100 6.811.0 −7.0% 63.0% 15 >100 6.8 6.1 16 45.9 3.3 7.0 9.4 13.6 17 35.1 6.110.2 10.8 55.7 18 >100 3.9 7.1 8.6 13.3 19 41.7 3.9 3.3 4.3 15.3 20 >1003.9 2.9 4.5 5.6 21 43.2 3.9 6.0 5.8 14.8 22 35.2 3.9 3.8 10.1 22.3 2312.7 3.9 7.7 6.6 cell death 24 11.5 3.9 5.2 4.7 cell death 25 8.4 3.95.8 7.0 cell death 26 9.7 3.9 3.6 6.6 cell death 27 >100 6.5 9.8 8.714.3 28 >100 6.5 7.7 9.2 7.9 29 >100 3.7 4.0 5.4 6.8 30 >100 3.7 4.2 4.04.2 31 >100 3.7 2.5 3.6 6.1 32 >100 3.7 5.5 5.2 5.3 33 >100 3.7 3.8 3.34.3 34 >100 3.7 4.5 3.7 7.0 35 >100 3.7 5.0 4.2 3.4 36 >100 5.5 5.5 5.84.8 37 32.8 5.5 5.8 7.5 15.0 38 >100 5.5 5.9 5.1 6.4 39 >100 6.0 6.2 7.18.2 40 >100 6.0 7.0 5.1 7.2 41 >100 6.0 8.3 10.2 14.4 42 23.7 4.4 4.38.7 19.1 43 100 4.4 3.0 4.3 7.6 44 >100 4.2 4.5 5.2 14.8 45 >100 3.8 3.04.0 3.5 46 >100 3.8 3.8 3.6 5.4 47 130.1 3.8 2.8 3.8 5.3 48 8.6 3.8 4.36.8 cell death 49 5.1 3.8 9.3 13.7 cell death 50 6.7 3.8 8.3 11.5 celldeath 51 6.6 3.8 12.5 15.2 cell death 52 6.8 3.8 9.4 15.0 cell death 536.1 3.8 9.2 13.9 cell death 54 6.7 3.8 4.9 8.9 cell death 55 10.4 3.83.5 5.3 cell death 56 48.8 2.6 2.7 4.8 15.4 57 2.5 2.6 6.7 12.1 celldeath 58 2.3 2.6 2.5 6.0 cell death 59 2.3 2.6 9.3 13.3 cell death 6015.4 2.7 4.6 7.8 80.9 61 12.6 2.7 6.4 11.8 12.3 62 2.8 2.7 8.5 26.6 celldeath 63 2.8 2.7 15.1 22.9 cell death 64 36.1 2.7 2.2 4.4 31.4 65 2.52.7 15.0 20.1 cell death 66 >100 4.5 3.3 3.7 4.1 67 147.2 4.5 3.2 2.94.8 68 >100 4.5 4.2 4.4 4.4 69 >100 3.3 5.6 4.7 5.3 70 >100 4.1 3.5 4.05.4 71 >100 3.7 3.8 4.3 5.8 72 37.7 4.1 5.4 6.6 19.1 73 >100 3.7 3.9 4.59.1 74 48.3 3.7 4.9 5.3 8.3 75 >100 3.7 3.5 3.6 5.3 76 42.1 3.2 4.5 4.78.8 77 50.6 3.7 4.5 5.7 13.9 78 58.3 3.6 3.4 3.4 3.8 79 7.9 4.1 7.8 11.7cell death 80   3%   1% 81 82  7.7%  6.3% 83 84 85  −6%  31% 86 87  3.2%−7.2% 88 89 90 91 92 ND 5.3 21.1 93 ND 5.3 6.5 94 104.7 6.8 9.0 95 14.18.5 4.9 6.8 23.6 96 8.2 97 7.5 98 49.2 6.1 7.2 9.6 37.5 99 >100 5.8 4.02.9 3.6 100 >100 6.5 7.1 9.0 8.0 101 >100 3.7 4.1 3.6 5.9 102 >100 4.34.8 2.8 6.8 103 36.0% −43.0%  104 31.3% −8.3% 105 25.1% −25.5%  106−6.6% −7.5% 107 −4.4% −8.9% 108 ND 5.3 3.9 109 42.5 6.6 8.2 9.9 10.3 11097.2 5.3 3.9 111 35.7 8.2 11.4 12.1 30.2 112 >100 6.8 10.6 113 72.7 8.29.9 10.1 28.6 −3.0% −24.0%  114 117.7 6.8 6.1 115 >100 6.1 4.8 116 101.46.8 25.9  0.0% −24.0%  117 >100 6.1 6.2 118 >100 6.1 6.0 119 3.5 6.6 6.98.8 8.5 120 >100 6.8 8.1 121 >100 4.4 9.0 122 >100 6.1 5.9 13.3% 15.5%123 >100 7.1 6.6 7.5 12.6 124 56.7 4.4 8.4 125 >100 4.4 5.0 126 >100 4.46.1 6.4 10.7 127 >100 4.4 5.8 10.2%   7% 128 >100 6.6 7.6 7.1 8.8129 >100 6.6 9.2 7.0 11.4 130 >100 4.4 8.8 131 >100 4.4 17.6 132 >1006.6 6.1 6..5 8.1 39.3% 44.7% 133 >100 4.4 7.1 134 >100 4.4 16.2 135 >1004.4 4.2 136 >100 4.4 5.9 137 >100 3.3 4.1 7.3 11.9 138 >100 3.3 3.7 3.74.2 139 >100 7.1 5.7 5.8 10.9 140 100.0 6.6 6.2 6.6 8.7 141 >100 6.6 5.66.1 10.3 142 73.6 6.6 4.7 6.0 7.2 143 123.7 5.5 5.5 5.7 7.2 144  47%  7% 145 146  109%  28% 147  74%  126% 148   1%  160% 149  20%  36% 150 105%  125% 151 6.4 9.4 7.7 11.2 152 6.4 7.9 8.1 8.6 153 6.4 8.0 6.8 6.3154 >100 2.0 2.9 2.9 2.8 155 >100 2.0 3.3 2.8 3.9 156 >100 2.0 3.6 2.64.9 157 2.39 4.17 2.68 2.00 158 2.39 3.11 2.49 3.75 159 2.35 2.17 2.353.02 160 2.35 2.51 2.65 2.84 161 2.35 3.03 2.73 4.06 162 3.21 4.41 4.047.34 163 3.21 4.07 3.76 4.48 164 3.21 2.89 3.43 2.77  −1%   9% 165 3.213.80 4.36 9.16

1. A guanidine derivative compound selected from the group consisting ofthe following compounds: 1) N1,N1-dimethyl-N5-piperidine biguanide, 2)N1-piperidin-N5-piperidine biguanide, 3)N1,N1-dimethyl-N5-methyl-N5-1-(naphthalen-1-yl)methyl biguanide, 4)N1,N1-dimethyl-N5-(benzo[d][1,3]dioxol-5-yl)methyl biguanide, 5)N1-piperidin-N5-pyrrolidine biguanide, 6)N1-isopropyl-N5-1-(pyridin-3-yl)methyl biguanide, 7)N1,N1-dipropyl-N5-propyl-N5-ethyl biguanide, 8)N1,N1-dipropyl-N5-piperidine biguanide, 9)N1-piperidin-N5-(benzo[d][1,3]dioxol-5-yl)methyl biguanide, 10)N1-(4-chloro)phenyl-N5-t-butyl-N5-benzyl biguanide, 11)N1-(3-bromo)phenyl-N5-(3-bromo)phenyl biguanide, 12)N1-piperidin-N5-(2-chloro)benzyl biguanide, 13)N1-piperidin-N5-(4-chloro)phenethyl biguanide, 14)N1-piperidin-N5-(2-chloro)phenethyl biguanide, 15)N1,N1-dipropyl-N5,N5-dicyclohexyl biguanide, 16)N1,N1-dipropyl-N5,N5-dipropyl biguanide, 17)N1-isopropyl-N5-(4-chloro)phenyl biguanide, 18)N1-(4-methyl)piperazin-N5-(4-trifluoromethyl)benzyl biguanide, 19)N1-(4-methyl)piperazin-N5-(4-trifluoromethyl)phenyl biguanide, 20)N1-(4-methyl)piperazin-N5-(3-trifluoromethyl)benzyl biguanide, 21)N1-(4-methyl)piperazin-N5-(3-trifluoromethyl)phenyl biguanide, 22)N1-(4-methyl)piperazin-N5-(3-trifluoromethoxy)phenyl biguanide, 23)N1-(4-ethoxy)piperidin-N5-(4-trifluoromethyl)phenyl biguanide, 24)N1-(4-ethoxy)piperidin-N5-(3-trifluoromethyl)phenyl biguanide, 25)N1-(4-ethoxy)piperidin-N5-(3-trifluoromethoxy)phenyl biguanide, 26)N1-(4-ethoxy)piperidin-N5-(4-trifluoromethoxy)phenyl biguanide, 27)N1-(4-methyl)piperazin-N5-(4-chloro)phenyl biguanide, 28)N1-(4-methyl)piperazin-N5-(3-fluoro)phenyl biguanide, 29)N1-(4-methyl)piperazin-N5-(3-chloro)phenyl biguanide, 30)N1-(4-methyl)piperazin-N5-(2-chloro)phenyl biguanide, 31)N1-(4-methyl)piperazin-N5-(4-chloro)benzyl biguanide, 32)N1-(4-methyl)piperazin-N5-(2-chloro)benzyl biguanide, 33)N1-(4-methyl)piperazin-N5-(4-fluoro)phenyl biguanide, 34)N1-(4-methyl)piperazin-N5-(2-fluoro)phenyl biguanide, 35)N1-(4-methyl)piperazin-N5-(3-chloro)benzyl biguanide, 36)N1-(4-methyl)piperazin-N5-butyl biguanide, 37)N1-(4-methyl)piperazin-N5-(3,4-dichloro)phenyl biguanide, 38)N1-(4-methyl)piperazin-N5-(3,4-difluoro)phenyl biguanide, 39)N1-(4-methyl)piperazin-N5-(3,5-difluoro)phenyl biguanide, 40)N1-(4-methyl)piperazin-N5-(3,4,5-trifluoro)phenyl biguanide, 41)N1-(3-pyridine)-N5-(3-trifluoromethyl)phenyl biguanide, 42)N1-3-pyridin-N5-(3-trifluoromethoxy)benzyl biguanide, 43)N1-3-pyridin-N5-(3-trifluoromethyl)benzyl biguanide, 44)N1-(3-methyl)piperidin-N5-cyclopentyl biguanide, 45)N1-(3-methyl)piperidin-N5-(4-methoxy)piperidine biguanide, 46)N1-(3-methyl)piperidin-N5-(4-ethoxy)piperidine biguanide, 47)N1-(3-methyl)piperidin-N5-pyrazin-2yl biguanide, 48)N1-(4-methyl)piperidin-N5-(4-bromo)phenyl biguanide hydrochloride, 49)N1-(4-methyl)piperidin-N5-(3-trifluoromethoxy)phenyl biguanide, 50)N1-(4-methyl)piperidin-N5-(3-trifluoromethyl)phenyl biguanide, 51)N1-(3-methyl)piperidin-N5-(3-trifluoromethyl)phenyl biguanide, 52)N1-(4-methyl)piperidin-N5-(4-trifluoromethoxy)phenyl biguanide, 53)N1-(4-methyl)piperidin-N5-(4-trifluoromethyl)phenyl biguanide, 54)N1-(4-methyl)piperidin-N5-(3-trifluoromethyl-4-fluoro)phenyl biguanide,55) N1-(4-methyl)piperidin-N5-(4-chloro)phenyl biguanide, 56)N1-(4-methyl)piperidin-N5-(4-fluoro)phenyl biguanide, 57)N1-(4-methyl)piperidin-N5-(3-fluoro-4-trifluoromethyl)phenyl biguanide,58) N1-(4-methyl)piperidin-N5-(3-trifluoromethyl-4-chloro)phenylbiguanide, 59)N1-(4-methyl)piperidin-N5-(3-fluoro-4-trifluoromethoxy)phenyl biguanide,60) N1-(4-methyl)piperidin-N5-(3-trifluoromethyl)benzyl biguanide, 61)N1-(4-methyl)piperidin-N5-(4-trifluoromethyl)benzyl biguanide, 62)N1-(3,5-dimethyl)piperidin-N5-(4-trifluoromethoxy)phenyl biguanide, 63)N1-(3,5-dimethyl)piperidin-N5-(4-trifluoromethyl)phenyl biguanide, 64)N1-(3,5-dimethyl)piperidin-N5-(4-fluoro)phenyl biguanide, 65)N1-(3,5-dimethyl)piperidin-N5-(3-trifluoromethyl-4-fluoro)phenylbiguanide, 66) N1-2,5-dihydro-1H-pyrrol-N5-pyridin-3-yl biguanide, 67)N1-2,5-dihydro-1H-pyrrol-N5-2,5-dihydro-1H-pyrrole biguanide, 68)N1-1,2,3,6-tetrahydropyridin-N5-1,2,3,6-tetrahydropyridine biguanide,69) N1-(4-methyl)piperidin-N5-(4-aminoethyl)phenyl biguanide, 70)N1-pyrrolidin-N5-(4-acetyl)phenyl biguanide, 71)N1-piperidin-N5-(4-morpholin-4-yl)phenyl biguanide, 72)N1-pyrrolidin-N5-(4-bromo)phenyl biguanide, 73)N1-piperidin-N5-(4-methoxy)phenyl biguanide, 74)N1-piperidin-N5-(2-propyl)phenyl biguanide, 75)N1-pyrrolidin-N5-(2-trifluoromethyl)phenyl biguanide, 76)N1-pyrrolidin-N5-(2-chloro-5-trifluoromethyl)phenyl biguanide, 77)N1-pyrrolidin-N5-(3-chloro-4-fluoro)phenyl biguanide, 78)N1-pyrrolidin-N5-(2,3-dichloro)phenyl biguanide, 79)N1-pyrrolidin-N5-(4-trifluoromethylthio)phenyl biguanide, 80)N1-pyrrolidin-N5-(2,6-difluoro)phenyl biguanide, 81)(3-(3-(imino(piperidin-1-yl)methyl)guanidino)benzyl)triphenylphosphoniumchloride, 82) N1-pyrrolidin-N5-methyl-N5-(4-trifluoromethoxy)phenylbiguanide, 83) N1-pyrrolidin-N5-(4-phenoxy)phenyl biguanide, 84)N1,N1-dimethyl-N5-(4-trifluoromethoxy)phenyl biguanide, 85)N1,N1-dimethyl-N5-methyl-N5-(4-trifluoromethoxy)phenyl biguanide, 86)N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N5-(2-thiophen-2-yl)ethylbiguanide, 87) N1-(N-acetyl)piperazin-N5-(4-trifluoromethoxy)phenylbiguanide, 88) N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N5-butyl biguanide,89) N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N5-phenethyl biguanide, 90)N1-(4,4-difluoro)piperidin-N5-(3,4-dichloro)phenyl biguanide, 91)N1-(4,4-difluoro)piperidin-N5-5,6,7,8-tetrahydronaphthalen-2-ylbiguanide, 92) N1-butyl-N2-cycloheptyl biguanide, 93)N1,N1-dimethyl-N2-(4-fluoro)benzyl-N5-piperidine biguanide, 94)N1-phenyl-N2-phenethyl biguanide, 95) N1-phenethyl-N2-(4-bromo)phenylbiguanide, 96) N1-benzyl-N2-methyl-N5,N5-dimethyl biguanide, 97)N1-phenethyl-N2-methyl-N5,N5-dimethyl biguanide, 98)N1-(4-chloro)benzyl-N2-cycloheptyl biguanide, 99)N1-piperidin-N2-(2-thiophen-2-yl)ethyl biguanide, 100)N1-(benzo[d][1,3]dioxol-5-yl)methyl-N2-ethyl biguanide, 101)N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N2-ethyl biguanide, 102)N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl-N2-methyl biguanide, 103)N1-(2-thiophen-2-yl)ethyl-N2-phenethyl biguanide, 104)N1-(2-thiophen-2-yl)ethyl-N2-2-(benzo[d][1,3]dioxol-5-yl)ethylbiguanide, 105) N1-(4-trifluoromethoxy)phenyl-N2-methyl-N5-pyrrolidinebiguanide, 106)N1-methyl-N1-(4-trifluoromethoxy)phenyl-N2-methyl-N5-pyrrolidinebiguanide, 107) N1-(benzo[d][1,3]dioxol-5-yl)methyl-N2-cyclopentylbiguanide, 108) N1-methyl biguanide, 109) N1-hexyl biguanide, 110)N1-(4-chloro)phenyl biguanide, 111) N1-(2-propene) biguanide, 112)N1-(benzo[d][1,3]dioxol-5-yl)methyl biguanide, 113) N1-phenyl biguanide,114) N1-propyl biguanide, 115) N1,N1-diisopropyl biguanide, 116)N1-(4-bromo)phenyl biguanide, 117) N1-(4-acetyl)phenyl biguanide, 118)N1-morpholin-4-yl biguanide, 119) N1-(2-trifluoromethyl)phenylbiguanide, 120) N1-(4-methoxy)phenyl biguanide, 121) N1-(2-propyl)phenylbiguanide, 122) N1-(4-morpholin-4-yl)phenyl biguanide, 123)N1-piperidine biguanide, 124) N1-benzyl biguanide, 125)N1-4-(N-acetylamino)phenyl biguanide, 126) N1-pyrrolidine biguanide,127) N1-4-(pyridin-2-yl)piperazine biguanide, 128)N1-(4-trifluoromethyl)phenyl biguanide, 129) N1-(4-chloro)benzylbiguanide, 130) N1,N1-dibenzyl biguanide, 131) N1-(4-methoxy)benzylbiguanide, 132) N1-(4-fluoro)benzyl biguanide, 133) N1,N1-dihexylbiguanide, 134) N1-methyl-N1-butyl biguanide, 135)N1-methyl-N1-cyclohexyl biguanide, 136) N1,N1-dicyclohexyl biguanide,137) N1-(4-chloro)phenethyl biguanide, 138) N1-(4-hydroxy)phenethylbiguanide, 139) N1-azepane biguanide, 140) N1-(4-trifluoromethoxy)phenylbiguanide, 141) N1-(4-trifluoromethyl)benzyl biguanide, 142)N1-(4-trifluoromethoxy)benzyl biguanide, 143)N1-2-(benzo[d][1,3]dioxol-5-yl)ethyl biguanide, 144)N1-(furan-2-yl)methyl biguanide, 145) N1-(2-thiophen-2-yl)ethylbiguanide, 146) N1-(2-fluoro-4-hydroxy)benzyl biguanide, 147)N1-(4-fluoro)phenylpropyl biguanide, 148) N1-(4-methoxy)phenylpropylbiguanide, 149) N1-(2-iodo)benzyl biguanide, 150) N1-(3-iodo)benzylbiguanide, 151)N-(6,6-dimethyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,152) 1-(6,6-dimethyl-4-oxo-1,4,5,6-tetrahydropyrimidin-3-yl)guanidine,153) N-(1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,154)N-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,155)N-(5-methyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,156)N-(4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,157)N-(6-cyclopropyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamidehydrochloride, 158)N-(5-methyl-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,159)N-(6-isopropyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,160) 1-(5-methyl-4-oxo-1,4,5,6-tetrahydropyrimidin-3-yl)guanidine, 161)N-(6-isobutyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,162)N-(4-methyl-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,163)N-(6-propyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide,164) 1-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrimidin-3-yl)guanidine, and165)N-(4-ethyl-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide;or a pharmaceutically acceptable salt thereof.
 2. The guanidinederivative compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein the pharmaceutically acceptable salt is a salt with anacid selected from the group consisting of formic acid, acetic acid,propionic acid, lactic acid, butyric acid, isobutyric acid,trifluoroacetic acid, malic acid, maleic acid, malonic acid, fumaricacid, succinic acid, succinic acid monoamide, glutamic acid, tartaricacid, oxalic acid, citric acid, glycolic acid, glucuronic acid ascorbicacid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid,benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid,dichloroacetic acid, aminooxy acetic acid, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonicacid, and boric acid.
 3. A pharmaceutical composition for preventing ortreating cancer comprising the compound of claim 1 or a pharmaceuticallyacceptable salt thereof as an active ingredient.
 4. The pharmaceuticalcomposition of claim 3, wherein the cancer is a disease selected fromthe group consisting of uterine cancer, breast cancer, stomach cancer,brain cancer, rectal cancer, colorectal cancer, lung cancer, skincancer, blood cancer, and liver cancer.
 5. The pharmaceuticalcomposition of claim 3, wherein the pharmaceutical composition isformulated into tablets, capsules, pills, granules, powders, injections,or liquids.
 6. A use of the compound of claim 1 or a pharmaceuticallyacceptable salt thereof for the preparation of a medicament for treatingcancer.
 7. The use of claim 6, wherein the cancer is a disease selectedfrom the group consisting of uterine cancer, breast cancer, stomachcancer, brain cancer, rectal cancer, colorectal cancer, lung cancer,skin cancer, blood cancer, and liver cancer.
 8. A method for preventingor treating cancer comprising administering a therapeutically effectiveamount of the compound of claim 1 or a pharmaceutically acceptable saltthereof to a subject in need thereof.
 9. The method of claim 8, whereinthe cancer is a disease selected from the group consisting of uterinecancer, breast cancer, stomach cancer, brain cancer, rectal cancer,colorectal cancer, lung cancer, skin cancer, blood cancer, and livercancer.